**Table 1.** *Trace elements levels reported in the literature for normal and abnormal human breast cancer using XRF techniques. the values are given in μg/g.*

**19**

*Role of Trace Elements in Breast Cancer and Their Characterization Using X-Ray Fluorescence…*

The qualitative and quantitative analysis of this technique requires an internal

relative to the net intensities found in the analyte by using the following equation

correspond to the relative sensitivity of the analyte/known standard solution.

( ) 4

=

*Z*x and

*z t*

The multi-element analysis of unknown samples can be obtained by using avail

able commercial peak fitting software GUPIXWIN (University of Guelph, Ontario,

*z*

*mzZ e P PZ*

σ ϕ

efficiency, integrated projectile charge, projectile charge, and Avogadro's number,

In this type of technique, the elemental concentration of unknown samples is

∈ *jk*

> *I* o

*jk* is the self-absorption correction factor which accounts for the absorption

of the incident and the emitted characteristic X-rays lying under the ith peak of

In the past, various researchers have reported a high level of iron in human breast cancer tissues as compared to the normal one [27–30, 35–38]. Elevated iron levels are also reported in in blood [32, 34] and scalp hair [39] of breast cancer patients using PIXE and WDXRF. Iron (Fe) plays a vital role in the human body

*I G*

*o jk jk jk <sup>N</sup>*

β σ

*k*th element,

∈

σ

=

*k*th element,

th X-rays of the

*i*

*m*

k denotes the concentration of

radiation incident on the sample visible to the detector,

*j*

th group of X-rays of

= *PP G U RR NS C C NS*

*U*) solution of known concentration with associating its concentration

U are the concentration of the analyte / known internal standard

U refer to the net intensity of the given analyte and

*x*

*N*A are the solid angle of the X-ray detector,

(4)

*jk* is the detector efficiency

*jk* is the X-ray fluores

*k*th element present in the sample,

*G* is the intensity of the exciting

*k*th element at the incident photon energy,

*x pA*

<sup>t</sup> *(Z)* is the counts of the X-ray fluorescent spectra for any atomic

*d eff QN* π

(2)


(3)

*N*jk is

*k*th


*S* <sup>R</sup>*/C* U

*DOI: http://dx.doi.org/10.5772/intechopen.95491*

*N* <sup>P</sup>*/ C*

*2.1.2 For TXRF*

Where,

*2.1.3 For PIXE*

The term

*2.1.4 For EDXRF*

number (Z),

respectively.

evaluated by

Where,

for the *j*

and β

the net rate for the

*m*

cence cross section of the

element within the target.

**3. Role of trace elements**

*j*

th X-ray energy of the

solution. The term

*C* <sup>G</sup>*/ C*

Canada) which is given as

*P*

*d*ϕ, *eff*p, *Q*,

standard (

#### *Trace Elements and Their Effects on Human Health and Diseases*

*Role of Trace Elements in Breast Cancer and Their Characterization Using X-Ray Fluorescence… DOI: http://dx.doi.org/10.5772/intechopen.95491*

#### *2.1.2 For TXRF*

*Trace Elements and Their Effects on Human Health and Diseases*

**18**

**Elements**

Normal Abnormal

Normal Abnormal

Normal Abnormal

Normal Abnormal

Normal Abnormal

Normal Abnormal

Normal Abnormal

Normal Abnormal

Normal Abnormal

Normal Abnormal

Normal Abnormal

**Table 1.**

2494.1

83

590.7

2631.6

1908 2132

7372.9

4309.5

3.0 4.4 *Trace elements levels reported in the literature for normal and abnormal human breast cancer using XRF techniques. the values are given in μg/g.*

127.4

100.6

294.8

1437.2

66.7

354.5

1618.6

4805.5

3164

131.5

**Na**

**Mg**

**P**

**S**

**Cl**

**K**

**Ca**

**Cr**

**Fe** 11.6 18.8 14.1 21.7

7 18.8

9.0 25.3

1.8

12.9

[30]

SR-XRF

0.6

3.8

0.95

7.7

[29]

SR-XRF, EDXRD

0.29

1.8

1

6.9

[29]

SR-XRF, EDXRD

0.3

2.9

438 1112

210 1032 726 2400

> 3999.9

6815.4

> 295

3240

1550.8

17 165 112 360 1975 2175

1320

2.9 18.6 10.4

355 1231.9

1885

3.4 8.7

3.3

11.4

[39]

PIXE

1.7

16.9

36.1

57.5

[32]

WDXRF

19.9

30.4

32.3

13

0.7

1.5

[34]

PIXE

291

24.6

38.5

0.9

2.5

56.3

19.5

9.8

0.07

0.8

[33]

SR-XRF

1259

3.2

28.1

14.8

19.2

0.06

1.7

1530

970

1270

153

480.2

52.7

376.3

5 98 32 147

27

64

35

31

14

39

—

—

—

6

8

[7]

EDXRF

[7]

TXRF

2

6

60.7

126.2

4.12

1.3

13.7

[37]

PIXE

1381.0

157.1

32.0

299.5

42.0

56.2

2.57

0.7

6.7

0.9

6.5

[27]

SR-XRF

0.3

2.7

**Cu**

**Zn**

**As**

**Se**

**Sr**

**Ref.**

**Analytical** 

**Technique**

The qualitative and quantitative analysis of this technique requires an internal standard (*U*) solution of known concentration with associating its concentration relative to the net intensities found in the analyte by using the following equation

$$\mathbf{C}\_{G} = \frac{\frac{\mathbf{N}\_{p}}{\mathbf{S}\_{p}}}{\frac{\mathbf{N}\_{R}}{\mathbf{S}\_{R}}} \mathbf{C}\_{U} \tag{2}$$

Where, *C*G*/ C*U are the concentration of the analyte / known internal standard solution. The term *N*P*/ C*U refer to the net intensity of the given analyte and *S*R*/C*<sup>U</sup> correspond to the relative sensitivity of the analyte/known standard solution.

#### *2.1.3 For PIXE*

The multi-element analysis of unknown samples can be obtained by using available commercial peak fitting software GUPIXWIN (University of Guelph, Ontario, Canada) which is given as

$$P\_x = P\_r(Z)\frac{4\pi mzZ\_\times e}{\sigma\_\times^z d\rho \epsilon \mathcal{J}\_p Q N\_A} \tag{3}$$

The term *P*t *(Z)* is the counts of the X-ray fluorescent spectra for any atomic number (Z), *d*ϕ, *eff*p, *Q*, *Z*x and *N*A are the solid angle of the X-ray detector, efficiency, integrated projectile charge, projectile charge, and Avogadro's number, respectively.

#### *2.1.4 For EDXRF*

In this type of technique, the elemental concentration of unknown samples is evaluated by

$$m\_i = \frac{N\_{\ne k}}{I\_o G \in\_{\ne k} \mathcal{B}\_{\ne k} \sigma\_{\ne k}} \tag{4}$$

Where, *m*k denotes the concentration of *k*th element present in the sample, *N*jk is the net rate for the *j* th group of X-rays of *k*th element, ∈ *jk* is the detector efficiency for the *j* th X-ray energy of the *k*th element, *I*o*G* is the intensity of the exciting radiation incident on the sample visible to the detector, σ *jk* is the X-ray fluorescence cross section of the *j* th X-rays of the *k*th element at the incident photon energy, and β *jk* is the self-absorption correction factor which accounts for the absorption of the incident and the emitted characteristic X-rays lying under the ith peak of *k*th element within the target.

#### **3. Role of trace elements**

In the past, various researchers have reported a high level of iron in human breast cancer tissues as compared to the normal one [27–30, 35–38]. Elevated iron levels are also reported in in blood [32, 34] and scalp hair [39] of breast cancer patients using PIXE and WDXRF. Iron (Fe) plays a vital role in the human body

and is an essential element. Normally, the human body contains 4–5 g of iron out of which 1 g is stored in the liver and spleen. The main component forms of iron, hemoglobin and myoglobin help in the growth of cells. The low and high dosage of iron cause various diseases like heart diseases, diabetes, anemia, cancer, listlessness, stomatitis, etc. and promote cancer which damage the tissues and convert hydrogen peroxide to free radical ions via Fenton and Haber-Weiss type reactions. These free radical ions cause DNA strand breaks, sister-chromatid and initiate lipid peroxidation which promotes the growth of cancer [40, 41].

An Element like copper (Cu) is involved in multiple biological processes which promote tumor growth. As far as the role of Cu in breast cancer is concerned, the picture comes out to be rather wavy. Morton K. Schwartz in his research also reported the role of trace elements in cancer [42]. The author mentioned that the Cu level in breast cancer tissue was greater than the normal one. Studies [27, 29, 30, 37, 38] using various techniques are in well agreement with past results. Many studies showed that the level of Cu and in blood serum [32, 34] and in hairs [39] of breast cancer patients are higher as compared to the normal one. The daily requirement of Cu intake is about 2 mg/day and heavy dose ingestion causes various diseases. The role of Cu and its concentration is well explained by many workers [43–45]. The toxicity and abnormal level of Cu element and metabolism processes present in the human blood cause the formation of blood vessels which further results in various types of cancer like breast, brain, gladder, etc. The extra formation of blood vessels in the human body is called Angiogenesis. It plays a vital role in the evolution of cancer cells inside the body. Since blood flows in the whole body, these cells also require blood for their growth, so it gives chemical signals to stimulate Angiogenesis. The matrix metalloproteinase (MMP) family of enzymes degrades the basement membrane and extracellular matrix of tissue inhibitors of metalloproteinase (TIMP). Under critical condition both MMP and TIMP imbalance the tissue and activate angiogenesis which caused breast cancer [46].

For zinc (Zn) element, the concentration of Zn in breast cancer case is slightly large as compared to the normal one. Similar trends were also reported by many researchers by using different techniques and methods [29, 30, 37, 38, 47, 48]. Depressed Zn levels are found in blood sera of breast cancer patients using PIXE [34] but higher levels in blood are found in [32] using WDXRF. This might be understood in terms of biochemical and histological differences between cancerous and normal blood. Like other elements, Zn also plays an important role in the biological, physiological and metabolic processes of the human blood. It is also obligatory for the formation and common function of the cell membrane. Toward the role in cancerous blood or tissues, the statement about the Zn is contradictory. Earlier reports suggested that the abnormal level of Zn leads to carcinogenesis [49]. These inconsistent annotations suggest that the role of Zn may vary from one to another organ depending on various factors like age group, lifestyle, environment changing and diet etc. However, in breast cancer case, level of Zn increases in cancer case rather than the normal case which is explained earlier. Lee et al. [50] also gave evidence on the behavior of Zn in human normal and cancer tissues. In their research, they suggested that the altered Zn homeostatic in breast cancer tissue is responsible for the increased level of Zn in the cancerous case which possibly leads to the growth of breast tumor. Zn is an important trace metal being a cofactor for more than 300 enzymes, and contributes to cellular signaling, proliferation, homeostasis, apoptosis [51, 52]. It is also a structural component of more than ~3000 proteins including metallothionein's, zinc transporters, p53 tumor suppressor and matrix metalloproteases which are involved in carcinogenesis and cancer progression [53]. In particular, p53 activation is important for apoptosis and cell cycle arrest in breast cancer case and protects women from it. Transcription factors,

**21**

development [58].

*Role of Trace Elements in Breast Cancer and Their Characterization Using X-Ray Fluorescence…*

e.g. nuclear factor-kappa (NF-κB) is activated in the breast cancer and leads to a more aggressive phenotype. Association of Zinc to breast cancer cell inhibits NF-κB [54]. Generally, the level of Zn in breast cancer cases is more. The reason behind them is that Zn is necessary for the cell production in a region adjacent to the tumor due to the presence of MMPs or tissue inhibitors of metalloproteinase. Similarly, the observed correlation between Cu and Zn shows that the ratio of Cu/Zn is more in

The element chromium (Cr) is also responsible for the formation of breast cancer in human body. Earlier reports suggested that level of trace elements of Cr in breast cancer tissues were significantly higher than the normal ones [37]. But in the research article given by Sarita et al. [34] using PIXE technique, the level of Cr in blood sera was found to be lower in breast cancer case as compared to the normal one. As we know that carcinogenic property of the trace elements depends mainly upon the factors like oxidation states and their chemical structure. In case of Cr element, the hexavalent chromium compounds Cr (VI) are more toxic than trivalent form Cr (III). Cr (VI) is easily absorbed by the body cells and then reduced to the trivalent form i.e. Cr (III). This reduction generates free active oxygen radical as well as glutathionyl radicals which further produces genotoxic effects which are

Chlorine (Cl) is an invasive chemical used in daily life products. It plays an important role in balancing the body cells and helps to digest the food. In the earlier study, the trends of the Cl element in human cancer tissue and blood were higher than the normal ones [32, 37]. Generally, Cl is present in extracellular fluid. Combination of Cl with organic compounds present in water or soil forms organochlorine. These are widely used as standard pesticides e.g. DDT, DDD, Isobenzan, Dicofol, Dieldrin, Eldrin, Lindane, BHC, etc. Carcinogenic and the weak estrogenic and anti-estrogenic hormonal effects of many organochlorines and their hydroxylated metabolites have led many researchers to hypothesize that they increase the risk of breast cancer in humans [56]. These are responsible for impairment or suppression of cell mediated immunity [57], mimicking androgenous hormones and modulating their as well as estrogen hormones metabolism prompting breast cancer

Since Ca is the major constituent of breast tissue calcification in the form of calcium hydroxyapatite, it has of vital importance in breast cancer. For the blood clotting mechanism, Ca plays an important role as factor IV. The Ca2+ cation is involved in various electrochemical mechanisms in the body like neutralization of charge, emulsion stabilization, free energy supply to the body cell. Magalhães et al. [38] mentioned the increased behavior of Ca in their research with TXRF technique. The same trend was also given by various workers with different methods and techniques [30, 37, 59, 60]. Higher Ca levels are found in the scalp hair and blood of breast cancer patients using PIXE and WDXRF in [32, 39]. Cationic calcium homeostasis in the plasma is tightly maintained through absorption, excretion and secretion and storage in bone. High level of calcium in the blood serum, known as hypercalcaemia, is associated with different types of cancer like breast cancer, lung cancer and myeloma, etc. These types of cancer result Ca to leak out from bones to the blood making it heavier than the normal one. This generally happens to the people suffering from cancer in the advance stage. Various analyses like meta-analysis and dose response analysis have been done to establish fact that there is a significant relation between Ca intake and breast cancer risk [61]. In these studies, the researchers suggested the dietary, lifestyle and intake dose of Ca which affect the human body. Having a complex nature, Ca intake is known to be inversely associated to breast cancer risk significantly in pre and postmenopausal women [62]. With rising cases of breast cancer being reported in the literature, the

*DOI: http://dx.doi.org/10.5772/intechopen.95491*

cancerous blood as compared to the normal blood [34, 48].

responsible for the formation of breast cancer [55].

#### *Role of Trace Elements in Breast Cancer and Their Characterization Using X-Ray Fluorescence… DOI: http://dx.doi.org/10.5772/intechopen.95491*

e.g. nuclear factor-kappa (NF-κB) is activated in the breast cancer and leads to a more aggressive phenotype. Association of Zinc to breast cancer cell inhibits NF-κB [54]. Generally, the level of Zn in breast cancer cases is more. The reason behind them is that Zn is necessary for the cell production in a region adjacent to the tumor due to the presence of MMPs or tissue inhibitors of metalloproteinase. Similarly, the observed correlation between Cu and Zn shows that the ratio of Cu/Zn is more in cancerous blood as compared to the normal blood [34, 48].

The element chromium (Cr) is also responsible for the formation of breast cancer in human body. Earlier reports suggested that level of trace elements of Cr in breast cancer tissues were significantly higher than the normal ones [37]. But in the research article given by Sarita et al. [34] using PIXE technique, the level of Cr in blood sera was found to be lower in breast cancer case as compared to the normal one. As we know that carcinogenic property of the trace elements depends mainly upon the factors like oxidation states and their chemical structure. In case of Cr element, the hexavalent chromium compounds Cr (VI) are more toxic than trivalent form Cr (III). Cr (VI) is easily absorbed by the body cells and then reduced to the trivalent form i.e. Cr (III). This reduction generates free active oxygen radical as well as glutathionyl radicals which further produces genotoxic effects which are responsible for the formation of breast cancer [55].

Chlorine (Cl) is an invasive chemical used in daily life products. It plays an important role in balancing the body cells and helps to digest the food. In the earlier study, the trends of the Cl element in human cancer tissue and blood were higher than the normal ones [32, 37]. Generally, Cl is present in extracellular fluid. Combination of Cl with organic compounds present in water or soil forms organochlorine. These are widely used as standard pesticides e.g. DDT, DDD, Isobenzan, Dicofol, Dieldrin, Eldrin, Lindane, BHC, etc. Carcinogenic and the weak estrogenic and anti-estrogenic hormonal effects of many organochlorines and their hydroxylated metabolites have led many researchers to hypothesize that they increase the risk of breast cancer in humans [56]. These are responsible for impairment or suppression of cell mediated immunity [57], mimicking androgenous hormones and modulating their as well as estrogen hormones metabolism prompting breast cancer development [58].

Since Ca is the major constituent of breast tissue calcification in the form of calcium hydroxyapatite, it has of vital importance in breast cancer. For the blood clotting mechanism, Ca plays an important role as factor IV. The Ca2+ cation is involved in various electrochemical mechanisms in the body like neutralization of charge, emulsion stabilization, free energy supply to the body cell. Magalhães et al. [38] mentioned the increased behavior of Ca in their research with TXRF technique. The same trend was also given by various workers with different methods and techniques [30, 37, 59, 60]. Higher Ca levels are found in the scalp hair and blood of breast cancer patients using PIXE and WDXRF in [32, 39]. Cationic calcium homeostasis in the plasma is tightly maintained through absorption, excretion and secretion and storage in bone. High level of calcium in the blood serum, known as hypercalcaemia, is associated with different types of cancer like breast cancer, lung cancer and myeloma, etc. These types of cancer result Ca to leak out from bones to the blood making it heavier than the normal one. This generally happens to the people suffering from cancer in the advance stage. Various analyses like meta-analysis and dose response analysis have been done to establish fact that there is a significant relation between Ca intake and breast cancer risk [61]. In these studies, the researchers suggested the dietary, lifestyle and intake dose of Ca which affect the human body. Having a complex nature, Ca intake is known to be inversely associated to breast cancer risk significantly in pre and postmenopausal women [62]. With rising cases of breast cancer being reported in the literature, the

*Trace Elements and Their Effects on Human Health and Diseases*

tion which promotes the growth of cancer [40, 41].

caused breast cancer [46].

and is an essential element. Normally, the human body contains 4–5 g of iron out of which 1 g is stored in the liver and spleen. The main component forms of iron, hemoglobin and myoglobin help in the growth of cells. The low and high dosage of iron cause various diseases like heart diseases, diabetes, anemia, cancer, listlessness, stomatitis, etc. and promote cancer which damage the tissues and convert hydrogen peroxide to free radical ions via Fenton and Haber-Weiss type reactions. These free radical ions cause DNA strand breaks, sister-chromatid and initiate lipid peroxida-

An Element like copper (Cu) is involved in multiple biological processes which promote tumor growth. As far as the role of Cu in breast cancer is concerned, the picture comes out to be rather wavy. Morton K. Schwartz in his research also reported the role of trace elements in cancer [42]. The author mentioned that the Cu level in breast cancer tissue was greater than the normal one. Studies [27, 29, 30, 37, 38] using various techniques are in well agreement with past results. Many studies showed that the level of Cu and in blood serum [32, 34] and in hairs [39] of breast cancer patients are higher as compared to the normal one. The daily requirement of Cu intake is about 2 mg/day and heavy dose ingestion causes various diseases. The role of Cu and its concentration is well explained by many workers [43–45]. The toxicity and abnormal level of Cu element and metabolism processes present in the human blood cause the formation of blood vessels which further results in various types of cancer like breast, brain, gladder, etc. The extra formation of blood vessels in the human body is called Angiogenesis. It plays a vital role in the evolution of cancer cells inside the body. Since blood flows in the whole body, these cells also require blood for their growth, so it gives chemical signals to stimulate Angiogenesis. The matrix metalloproteinase (MMP) family of enzymes degrades the basement membrane and extracellular matrix of tissue inhibitors of metalloproteinase (TIMP). Under critical condition both MMP and TIMP imbalance the tissue and activate angiogenesis which

For zinc (Zn) element, the concentration of Zn in breast cancer case is slightly large as compared to the normal one. Similar trends were also reported by many researchers by using different techniques and methods [29, 30, 37, 38, 47, 48]. Depressed Zn levels are found in blood sera of breast cancer patients using PIXE [34] but higher levels in blood are found in [32] using WDXRF. This might be understood in terms of biochemical and histological differences between cancerous and normal blood. Like other elements, Zn also plays an important role in the biological, physiological and metabolic processes of the human blood. It is also obligatory for the formation and common function of the cell membrane. Toward the role in cancerous blood or tissues, the statement about the Zn is contradictory. Earlier reports suggested that the abnormal level of Zn leads to carcinogenesis [49]. These inconsistent annotations suggest that the role of Zn may vary from one to another organ depending on various factors like age group, lifestyle, environment changing and diet etc. However, in breast cancer case, level of Zn increases in cancer case rather than the normal case which is explained earlier. Lee et al. [50] also gave evidence on the behavior of Zn in human normal and cancer tissues. In their research, they suggested that the altered Zn homeostatic in breast cancer tissue is responsible for the increased level of Zn in the cancerous case which possibly leads to the growth of breast tumor. Zn is an important trace metal being a cofactor for more than 300 enzymes, and contributes to cellular signaling, proliferation, homeostasis, apoptosis [51, 52]. It is also a structural component of more than ~3000 proteins including metallothionein's, zinc transporters, p53 tumor suppressor and matrix metalloproteases which are involved in carcinogenesis and cancer progression [53]. In particular, p53 activation is important for apoptosis and cell cycle arrest in breast cancer case and protects women from it. Transcription factors,

**20**

trace elements like phosphorus (P), sulfur (S), potassium (K) and sodium (Na) and their role should be of greater concern. From the literature, it has been seen that proportion of these elements in breast cancer human blood is slightly higher with respect to the normal human blood. Earlier reports found that the abnormal level of phosphorus may influence breast cancer [32]. Some studies reported a statistically elevated P content in breast tissue compared to normal one using TXRF [31, 38, 48]. The number of in-vitro studies suggested that for cell growth in human body, the inorganic phosphate (Pi) and phosphate are two responsible terms. They both act like a mitogen. This elevated value of Pi promotes cell prolific microenvironment which causes breast tumor. Another study by Wulaningsih and his co-workers showed that when the content of phosphorus along with calcium enters in the human body, it increases the estrogens level which promotes the growth of breast cancer [63, 64].

In a view of sulfur element role, it has been seen from the past studies that the concentration of the sulfur increased in cancerous blood as well as in cancerous tissue than normal ones [31, 32, 38]. Sulfur plays an important role in cell renewal and enables transferring of oxygen from cell membrane. It is widely used in biological processes which act as both fuel and respiratory materials for the human body. Sulfur has an important role in chemotherapy to reduce the size of the breast tumor which uses sulfur containing drugs like Docetaxel, Paclitaxel, Taxanes, Eribulin, etc. [65]. From the past studies, it has been seen that the sulfur is commonly used in some form like organic sulfur to treat cancer which is useful in anti-cancer therapy. The research also claims that the sulfur containing compounds work like an anticancer reagent which kills the cancer cells without affecting normal and healthy cells present in the whole body system. Furthermore, organic sulfur compounds like amino acid, methyl-sulfonyl methane and diallyl sulphide, etc. have powerful anti-cancer effect against breast cancer [66].

Elements like potassium (K) and sodium (Na), they both also play a key role in the biological processes present in the human body system. The literature clearly shows that the value of both potassium and sodium in human breast cancer cell and blood increases with respect to normal one [6, 29, 32, 38]. Earlier views on potassium element clearly show that the concentration in human affected from breast cancer is not significantly different from the normal one [37]. This twin behavior of potassium element might depend upon many factors like eating/drinking lifestyle, environment behavior, sample preparation etc. Also, it has been concluded that most of the research has been done on the cancer tissues which are generally not homogeneous. So, for multi-elements detection system and for obtaining better results, samples must be homogeneous. In order to understand the role of potassium element in the cancerous blood, we know that it acts as an electrolyte and present mainly in the form of k<sup>+</sup> ion (cation) inside the human blood. Acid–base and water balance in the tissues and blood is maintained with the help of K+ in the human body. The role of K<sup>+</sup> in regulating tumor cell proliferation and as anti-apoptotic and pro-apoptotic agent is well established [67]. On its combination with ascorbic acid, the inhibitory effect on the survival of breast cancer cell lines has been observed. Further details are given in Ref. [68]. On the other hand, in the case of sodium element, we clearly have seen from the past studies that the concentration of sodium element increases in case of breast cancer blood of human body [32]. The role of sodium (compound form) in cancerous blood is also a big concern. Since sodium is also present in the human blood in the cation form, it also plays an important role in the metabolism processes in the human body. Researchers reported the activity of Na+ /K+ adenosine tri-phosphate (ATP) which clearly explain the difference between the concentration of Na + and k + cation in cancerous cells and normal one [69]. Higher Na+ /K+ ratios have been reported in cancerous blood using WDXRF [32].

**23**

effect of free radicals.

*Role of Trace Elements in Breast Cancer and Their Characterization Using X-Ray Fluorescence…*

The recent research says that the sodium compound form i.e. sodium bicarbonate can be treated as an anti-cancer agent. The research proved that the use of sodium bicarbonate has been beneficial for breast and prostate cancer etc. Most of the work

Magnesium (Mg) is the second most abundant cation in the body which acts as an activator in about 300 enzymatic reactions. These reactions include conversion of ATP to ADP for cell energy metabolism, DNA replication and repair, protein synthesis, inflammation, proliferation, cell cycle control and apoptosis [70, 71]. Most of these factors are related to carcinogenesis. Progression of breast cancer is also related to Mg where in the proliferative phase of the disease, the neoplastic cells causes an influx of it and hence there is an increase in the intracellular concentration of Mg disturbing its homeostasis [72]. Several studies have investigated the direct association of high magnesium intake and breast cancer risk and an inverse relation has been found. Indirectly, higher Mg intake lowers the C Reactive Protein (CRP) level and decreases the breast cancer risk [73]. Some earlier reports suggested that a significantly low Mg level in serum found with respect to normal tissue [74] while high Mg levels are found in cancerous blood using WDXRF in [32]. It is also observed that the concentrations of magnesium in all blood samples are opposite to the concentration of calcium. Both calcium and magnesium compete for the transporter transient receptor potential melastatin 7 (TRPM7) for their absorption in the tumor membrane. A negative feedback mechanism regulates the level of both. It has been seen that reduced level of magnesium decreases the Mg-ATP levels inside the cell which leads to increase the Ca-ATP levels of the cell and this intracellular Ca increase leads to increased cell proliferation. Ca/Mg ratio is elevated in breast cancer case since Ca concentrations are increased while concentration of Mg

Selenium (Se) is the important trace mineral for the human body. It is believed that all the enzymes present in the human body system are selenium dependent. The abnormal level of selenium causes many diseases. As far as a disease like breast cancer is concerned, the picture of selenium is not clear. Different studies give different views on the role and presence of selenium in the human body. Using TXRF technique, Magalhães et al. [38] mentioned that the concentration of selenium element increased in breast cancer tissue as compared to the normal one. The observed high level of selenium in breast cancer tissue was also reported in the earlier studies also [37]. Low Se levels are found in the blood sera samples in [34]. In accordance with the hypothesis, finding suggested that the selenium worked as an immune enhancing and antioxidant to reduce the breast cancer [76]. Lifestyle, eating/drinking habits, environment, etc. are deciding factors because most of the selenium found in the human body is from eating/drinking habits etc. An inverse relationship exists between Selenium intake and risk of breast cancer [77]. Also, it might be guessed that it acts like an anti-cancerous agent. We know that selenium is generally absorbed in the body in the form of L-selenomethionine. Earlier studies confirmed that in MCF-7 breast cancer, the therapeutic effect of methyl selenocysteine combined with tamoxifen and imidoselenocarbamate considered as an antitumour agent reduces the growth of breast cancer [78, 79]. Combs et al*.* [80] in their research article suggested that selenium works as anti-oxidant effects via Glutathione peroxidise (GSH-Px) which further protects the body from damaging

Arsenic (As) is one of the most toxic elements found in nature. The main source of arsenic coming in our body is from eating/drinking habits, soil and from plants etc. However, its mechanism and role are not well explained but the epidemiological evidence in the past literature showed the toxicity of arsenic from drinking water causes different types of cancer. From the literature, it has been seen that the level

*DOI: http://dx.doi.org/10.5772/intechopen.95491*

was done on the mice.

is decreased [75].

The recent research says that the sodium compound form i.e. sodium bicarbonate can be treated as an anti-cancer agent. The research proved that the use of sodium bicarbonate has been beneficial for breast and prostate cancer etc. Most of the work was done on the mice.

Magnesium (Mg) is the second most abundant cation in the body which acts as an activator in about 300 enzymatic reactions. These reactions include conversion of ATP to ADP for cell energy metabolism, DNA replication and repair, protein synthesis, inflammation, proliferation, cell cycle control and apoptosis [70, 71]. Most of these factors are related to carcinogenesis. Progression of breast cancer is also related to Mg where in the proliferative phase of the disease, the neoplastic cells causes an influx of it and hence there is an increase in the intracellular concentration of Mg disturbing its homeostasis [72]. Several studies have investigated the direct association of high magnesium intake and breast cancer risk and an inverse relation has been found. Indirectly, higher Mg intake lowers the C Reactive Protein (CRP) level and decreases the breast cancer risk [73]. Some earlier reports suggested that a significantly low Mg level in serum found with respect to normal tissue [74] while high Mg levels are found in cancerous blood using WDXRF in [32]. It is also observed that the concentrations of magnesium in all blood samples are opposite to the concentration of calcium. Both calcium and magnesium compete for the transporter transient receptor potential melastatin 7 (TRPM7) for their absorption in the tumor membrane. A negative feedback mechanism regulates the level of both. It has been seen that reduced level of magnesium decreases the Mg-ATP levels inside the cell which leads to increase the Ca-ATP levels of the cell and this intracellular Ca increase leads to increased cell proliferation. Ca/Mg ratio is elevated in breast cancer case since Ca concentrations are increased while concentration of Mg is decreased [75].

Selenium (Se) is the important trace mineral for the human body. It is believed that all the enzymes present in the human body system are selenium dependent. The abnormal level of selenium causes many diseases. As far as a disease like breast cancer is concerned, the picture of selenium is not clear. Different studies give different views on the role and presence of selenium in the human body. Using TXRF technique, Magalhães et al. [38] mentioned that the concentration of selenium element increased in breast cancer tissue as compared to the normal one. The observed high level of selenium in breast cancer tissue was also reported in the earlier studies also [37]. Low Se levels are found in the blood sera samples in [34]. In accordance with the hypothesis, finding suggested that the selenium worked as an immune enhancing and antioxidant to reduce the breast cancer [76]. Lifestyle, eating/drinking habits, environment, etc. are deciding factors because most of the selenium found in the human body is from eating/drinking habits etc. An inverse relationship exists between Selenium intake and risk of breast cancer [77]. Also, it might be guessed that it acts like an anti-cancerous agent. We know that selenium is generally absorbed in the body in the form of L-selenomethionine. Earlier studies confirmed that in MCF-7 breast cancer, the therapeutic effect of methyl selenocysteine combined with tamoxifen and imidoselenocarbamate considered as an antitumour agent reduces the growth of breast cancer [78, 79]. Combs et al*.* [80] in their research article suggested that selenium works as anti-oxidant effects via Glutathione peroxidise (GSH-Px) which further protects the body from damaging effect of free radicals.

Arsenic (As) is one of the most toxic elements found in nature. The main source of arsenic coming in our body is from eating/drinking habits, soil and from plants etc. However, its mechanism and role are not well explained but the epidemiological evidence in the past literature showed the toxicity of arsenic from drinking water causes different types of cancer. From the literature, it has been seen that the level

*Trace Elements and Their Effects on Human Health and Diseases*

anti-cancer effect against breast cancer [66].

mainly in the form of k<sup>+</sup>

body. The role of K<sup>+</sup>

cancer [63, 64].

trace elements like phosphorus (P), sulfur (S), potassium (K) and sodium (Na) and their role should be of greater concern. From the literature, it has been seen that proportion of these elements in breast cancer human blood is slightly higher with respect to the normal human blood. Earlier reports found that the abnormal level of phosphorus may influence breast cancer [32]. Some studies reported a statistically elevated P content in breast tissue compared to normal one using TXRF [31, 38, 48]. The number of in-vitro studies suggested that for cell growth in human body, the inorganic phosphate (Pi) and phosphate are two responsible terms. They both act like a mitogen. This elevated value of Pi promotes cell prolific microenvironment which causes breast tumor. Another study by Wulaningsih and his co-workers showed that when the content of phosphorus along with calcium enters in the human body, it increases the estrogens level which promotes the growth of breast

In a view of sulfur element role, it has been seen from the past studies that the concentration of the sulfur increased in cancerous blood as well as in cancerous tissue than normal ones [31, 32, 38]. Sulfur plays an important role in cell renewal and enables transferring of oxygen from cell membrane. It is widely used in biological processes which act as both fuel and respiratory materials for the human body. Sulfur has an important role in chemotherapy to reduce the size of the breast tumor which uses sulfur containing drugs like Docetaxel, Paclitaxel, Taxanes, Eribulin, etc. [65]. From the past studies, it has been seen that the sulfur is commonly used in some form like organic sulfur to treat cancer which is useful in anti-cancer therapy. The research also claims that the sulfur containing compounds work like an anticancer reagent which kills the cancer cells without affecting normal and healthy cells present in the whole body system. Furthermore, organic sulfur compounds like amino acid, methyl-sulfonyl methane and diallyl sulphide, etc. have powerful

Elements like potassium (K) and sodium (Na), they both also play a key role in the biological processes present in the human body system. The literature clearly shows that the value of both potassium and sodium in human breast cancer cell and blood increases with respect to normal one [6, 29, 32, 38]. Earlier views on potassium element clearly show that the concentration in human affected from breast cancer is not significantly different from the normal one [37]. This twin behavior of potassium element might depend upon many factors like eating/drinking lifestyle, environment behavior, sample preparation etc. Also, it has been concluded that most of the research has been done on the cancer tissues which are generally not homogeneous. So, for multi-elements detection system and for obtaining better results, samples must be homogeneous. In order to understand the role of potassium element in the cancerous blood, we know that it acts as an electrolyte and present

pro-apoptotic agent is well established [67]. On its combination with ascorbic acid, the inhibitory effect on the survival of breast cancer cell lines has been observed. Further details are given in Ref. [68]. On the other hand, in the case of sodium element, we clearly have seen from the past studies that the concentration of sodium element increases in case of breast cancer blood of human body [32]. The role of sodium (compound form) in cancerous blood is also a big concern. Since sodium is also present in the human blood in the cation form, it also plays an important role in the metabolism processes in the human body. Researchers reported the activity of

adenosine tri-phosphate (ATP) which clearly explain the difference between

ratios have been reported in cancerous blood using WDXRF [32].

the concentration of Na + and k + cation in cancerous cells and normal one [69].

balance in the tissues and blood is maintained with the help of K+

ion (cation) inside the human blood. Acid–base and water

in regulating tumor cell proliferation and as anti-apoptotic and

in the human

**22**

Na+ /K+

Higher Na+

/K+

of arsenic is higher in breast cancer tissue as compared to others by using XRF techniques [37]. Lower serum As concentrations are found in [34]. The reason behind this is that the arsenite generates the effect of estradiol and induces ROS growth, DNA damage and increases c-Myc and heme oxygenase (HO-1) protein levels which lead to tumor cell proliferation and increase in the estrogens level in the body and causes breast cancer in MCF-7 cells. The c-Myc is one of the most commonly activated genes present in advance stages of breast cancer. The study shows that arsenite present in breast cancer MCF-7 cells increases the c-Myc and HO-1 level which results in DNA damage. The high increases in c-Myc and HO-1 level further deactivate the p53 gene and affect the metabolism and biological process if the body results in breast cancer [81]. On the other hand, arsenic trioxide has an antiproliferative effect on human breast cancer MCF-7 cells due to reduction of HERG channels and activation of caspase-3. Generally, HERG belongs to multi-genetic family of voltage gate k + channels and present mostly in the tumor cells, not in normal cells of the human body system [82].

For Strontium, the Department of Health and Human Services determined that stable isotopes of strontium do not play any role in cancer. Its radioactive isotopes 89Sr and 90Sr are important for breast cancer. Earlier studies mentioned the higher level of strontium in breast cancer tissue as compared to the normal tissue [37]. However, the IARC clearly suggested the carcinogenic behavior of radioactive strontium (90Sr) which may cause cancer. The reason is that when 90Sr enters in the body it gets mostly attached on the surface of the bone and soft tissue itself. Due to high dose and radioactive decay property, it combines with the blood or tissue and damages the DNA structure. In the case of 89Sr, the previous study showed that it is more beneficial in breast cancer patients with metastatic bone pain and have similar metabolism function as that of calcium [83].

#### **Acknowledgements**

Author (H. S. Kainth) acknowledges the financial support received from University Grant Commission (UGC) New-Delhi, grant number F.4-2/2006 (BSR)/PH/18-19/0084, in the form of D. S. Kothari post-doctorate fellowship.

**25**

**Author details**

and Sanjiv Puri1

Harpreet Singh Kainth1

\*, Deeksha Khandelwal<sup>2</sup>

3 Department of Radiotherapy, PGIMER, Chandigarh, India

4 Department of Physics, Punjabi University, Patiala, India

provided the original work is properly cited.

\*Address all correspondence to: harpreet.2january@gmail.com

1 Department of Basic and Applied Sciences, Punjabi University, Patiala, India

2 Inter University Accelerator Centre, Aruna Asaf Ali Marg, New Delhi, India

© 2020 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

, Ranjit Singh3

, Gurjeet Singh4

*Role of Trace Elements in Breast Cancer and Their Characterization Using X-Ray Fluorescence…*

*DOI: http://dx.doi.org/10.5772/intechopen.95491*

*Role of Trace Elements in Breast Cancer and Their Characterization Using X-Ray Fluorescence… DOI: http://dx.doi.org/10.5772/intechopen.95491*

#### **Author details**

*Trace Elements and Their Effects on Human Health and Diseases*

of the human body system [82].

**Acknowledgements**

metabolism function as that of calcium [83].

of arsenic is higher in breast cancer tissue as compared to others by using XRF techniques [37]. Lower serum As concentrations are found in [34]. The reason behind this is that the arsenite generates the effect of estradiol and induces ROS growth, DNA damage and increases c-Myc and heme oxygenase (HO-1) protein levels which lead to tumor cell proliferation and increase in the estrogens level in the body and causes breast cancer in MCF-7 cells. The c-Myc is one of the most commonly activated genes present in advance stages of breast cancer. The study shows that arsenite present in breast cancer MCF-7 cells increases the c-Myc and HO-1 level which results in DNA damage. The high increases in c-Myc and HO-1 level further deactivate the p53 gene and affect the metabolism and biological process if the body results in breast cancer [81]. On the other hand, arsenic trioxide has an antiproliferative effect on human breast cancer MCF-7 cells due to reduction of HERG channels and activation of caspase-3. Generally, HERG belongs to multi-genetic family of voltage gate k + channels and present mostly in the tumor cells, not in normal cells

For Strontium, the Department of Health and Human Services determined that stable isotopes of strontium do not play any role in cancer. Its radioactive isotopes 89Sr and 90Sr are important for breast cancer. Earlier studies mentioned the higher level of strontium in breast cancer tissue as compared to the normal tissue [37]. However, the IARC clearly suggested the carcinogenic behavior of radioactive strontium (90Sr) which may cause cancer. The reason is that when 90Sr enters in the body it gets mostly attached on the surface of the bone and soft tissue itself. Due to high dose and radioactive decay property, it combines with the blood or tissue and damages the DNA structure. In the case of 89Sr, the previous study showed that it is more beneficial in breast cancer patients with metastatic bone pain and have similar

Author (H. S. Kainth) acknowledges the financial support received from University Grant Commission (UGC) New-Delhi, grant number F.4-2/2006 (BSR)/PH/18-19/0084, in the form of D. S. Kothari post-doctorate fellowship.

**24**

Harpreet Singh Kainth1 \*, Deeksha Khandelwal<sup>2</sup> , Ranjit Singh3 , Gurjeet Singh4 and Sanjiv Puri1


\*Address all correspondence to: harpreet.2january@gmail.com

© 2020 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

## **References**

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[2] Brinton LA, Gaudet MM, Gierach GL. Breast cancer. In: Thun MJ, Linet MS, Cerhan JR, Haiman CA, Schottenfeld D, editors. Cancer Epidemiology and Prevention. 4th ed. New York: Oxford University Press;2018. p. 861-888. DOI: 10.1093/ oso/9780190238667.001.0001

[3] Liou G-Y, Storz P. Reactive oxygen species in cancer. Free Radical Research. 2010; 44(5):1-31*.* DOI: 10.3109/10715761003667554

[4] Reddy S, Charles M, Naga Raju G, Byreddy S, Reddy T, Lakshmi P, Vijayan, V. Trace Elemental Analysis of Cancer-Afflicted Intestine by PIXE Technique. Biological trace element research. 2004; 102:265-282. DOI: 10.1385/bter:102:1-3:265

[5] Czarnowski D V, Denkhaus E, Lemke K. Determination of trace element distribution in cancerous and normal human tissues by total X-ray fluorescence analysis. Spec. Acta B. 1997; 52(7):1047-1052. DOI: 10.1016/ S0584-8547(96)01625-4

[6] Milde D, Altmannová K, Vysloužil K, Stužka V. Trace Element Levels in Blood Serum and Colon Tissue in Colorectal Cancer. Chemical Papers. 2005; 59(3): 157-160. Corpus ID: 17410947

[7] Magalhães T, Bohlen A V, Carvalho M L, Becker M. Trace elements in human cancerous and healthy tissues from the same individual: A comparative study by TXRF and EDXRF. Spec. Acta Part B. 2006; 61:1185-1193. DOI: 10.1016/j. sab.2006.06.002

[8] Benninghoff L, Czarnowski D V, Denkhaus E, Lemke K. Analysis of human tissues by total reflection X-ray fluorescence. Application of chemometrices for diagnostic cancer recognition. Spec. Acta Part B. 1997; 52:1039-1046. DOI: 10.1016/ S0584-8547(96)01626-6

[9] Hernandez-Caraballo E A, Marco-Parra L M. Direct analysis of blood serum by total reflection X-ray fluorescence spectrometry and application of an artificial neutral network approach for cancer diagnosis. Spec. Acta Part B. 2003; 58:2195-2201. DOI: 10.1016/j.sab.2003.07.003

[10] Dyson N. X-rays in Atomic and Nuclear Physics. 2nd ed. Cambridge: Cambridge University Press; 1990. DOI: 10.1017/CBO9780511470806

[11] Jenkins R, Gould R W, Gedcke D. Quantitative X-ray spectrometry. CRC Press; 1995. DOI: 10.1201/9781482273380

[12] Stand-zenieks P, Selin E. Background reduction of X-ray fluorescence spectra in a secondary target energy dispersive spectrometer. Nucl. Inst. Methods Phys. Res., B Beam Interact. Mater. Atoms. 1979; 165: 63-70. DOI: 10.1016/0029-554X(79)90308-2

[13] Custódio P, Carvalho M L, Nunes F, Trace elements determination by energy dispersive X-ray fluorescence (EDXRF) in human placenta and membrane: A comparative study. Anal. Bional. Chem. 2003; 375:1101-1106. DOI: 10.1007/ s00216-003-1765-9

[14] Cesareo R, Castellano A, Buccolieri G, Quarta S, Marabelli M, Santopadre P, Leole M, Brunetti A, Portable equipment for energy dispersive X-ray fluorescence analysis of Giotto's frescoes in the Chapel of the Scrovegni, Nucl. Instrum. Methods

**27**

*Role of Trace Elements in Breast Cancer and Their Characterization Using X-Ray Fluorescence…*

research. 2009;102(2-3):241. DOI: 10.1007/s11120-009-9473-8

Sá J, Szlachetko J. A laboratorybased double X-ray spectrometer for simultaneous X-ray emission and X-ray absorption studies. Journal of Analytical Atomic Spectrometry. 2019;34(7):1409-

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Sons. 1988

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[25] Penner-Hahn JE. X-ray absorption spectroscopy. e LS. 2001. DOI: 10.1038/

[26] Al-Ebraheem A, Goettlicher J, Geraki K, Ralph S, Farquharson MJ. The determination of zinc, copper and iron oxidation state in invasive ductal carcinoma of breast tissue and normal surrounding tissue using XANES. X-Ray Spectrometry. 2010;39(5):332-337. DOI:

[27] Geraki K, Farquharson MJ, Bradley DA. Concentrations of Fe, Cu and Zn in breast tissue: a synchrotron XRF study. Physics in Medicine & Biology. 2002;47(13):2327-2339. DOI:

10.1088/0031-9155/47/13/310

[28] Geraki K, Farquharson MJ, Bradley DA. X-ray fluorescence and energy dispersive x-ray diffraction for the quantification of elemental concentrations in breast tissue. Physics in Medicine & Biology. 2003;49(1):99- 110. DOI: 10.1088/0031-9155/49/1/007

[29] Geraki K, Farquharson MJ, Bradley DA, Hugtenburg RP. A synchrotron XRF study on trace

S0168-583X(03)01672-0

elements and potassium in breast tissue. Nuclear Instruments and Methods in Physics Research Section B: Beam Interactions with Materials and Atoms. 2004;213:564-568. DOI: 10.1016/

*DOI: http://dx.doi.org/10.5772/intechopen.95491*

Phys. Res., B Beam Interact. Matter. Atoms. 2004; 213:703-706. DOI: 10.1016/S0168-583X(03)01758-0

[15] Wobrauschek P, Total reflection X-ray fluorescence analysis-a review, X-Ray Spectrom*. 2007;36:*289-300. DOI:

[16] Tsuji K, Emoto T, Matsuoka Y, Nagamura T, Ding X, Micro-xrf instrument developed in combination with atomic force microscope. Adv. X Ray Anal. 2005; 48:221-228. DOI:

[17] Buzanich G, Wobrauschek P, Streli C, Markowicz A, Wegrzynek D, Chinea-Cano E, Bamford S. A portable micro-X-ray fluorescence spectrometer with polycapillary optics and vacuum chamber for archaeometric and other applications. Spectrochimica Acta Part B: Atomic Spectroscopy. 2007;62(11):1252- 1256. DOI: 10.1016/j.sab.2007.08.003

[18] Lopes R T, Lima I, Pereria G R, Perez C A. Synchrotron radiation X-ray micro fluorescence techniques and biological applications. Pramana-J. Phys. 2011; 76:271-279. DOI: 10.1007/

[19] Johansson SA, Campbell J L. PIXE: A novel technique for elemental analysis. John Wiley & Sons, Chichester,

[20] Ryan C G. Quantitative Trace Element Imaging Using PIXE and the Nuclear Microprobe. John Wiley & Sons, North Ryde, Australia, 2001

[21] Ryan C G, Cousens D R, Sie S H, Griffin W L, Suter G F, Clayton E. Quantitative pixe microanalysis of geological matemal using the CSIRO proton microprobe. Nucl. Instru. Meth. Phy. Res. B. 1990; 47:55-71. DOI: 10.1016/0168-583X(90)90047-X

[22] Yano J, Yachandra VK. X-ray

absorption spectroscopy. Photosynthesis

10.1002/xrs.985

10.1154/1.1913724

s12043-011-0043-1

UK, 1988

*Role of Trace Elements in Breast Cancer and Their Characterization Using X-Ray Fluorescence… DOI: http://dx.doi.org/10.5772/intechopen.95491*

Phys. Res., B Beam Interact. Matter. Atoms. 2004; 213:703-706. DOI: 10.1016/S0168-583X(03)01758-0

[15] Wobrauschek P, Total reflection X-ray fluorescence analysis-a review, X-Ray Spectrom*. 2007;36:*289-300. DOI: 10.1002/xrs.985

[16] Tsuji K, Emoto T, Matsuoka Y, Nagamura T, Ding X, Micro-xrf instrument developed in combination with atomic force microscope. Adv. X Ray Anal. 2005; 48:221-228. DOI: 10.1154/1.1913724

[17] Buzanich G, Wobrauschek P, Streli C, Markowicz A, Wegrzynek D, Chinea-Cano E, Bamford S. A portable micro-X-ray fluorescence spectrometer with polycapillary optics and vacuum chamber for archaeometric and other applications. Spectrochimica Acta Part B: Atomic Spectroscopy. 2007;62(11):1252- 1256. DOI: 10.1016/j.sab.2007.08.003

[18] Lopes R T, Lima I, Pereria G R, Perez C A. Synchrotron radiation X-ray micro fluorescence techniques and biological applications. Pramana-J. Phys. 2011; 76:271-279. DOI: 10.1007/ s12043-011-0043-1

[19] Johansson SA, Campbell J L. PIXE: A novel technique for elemental analysis. John Wiley & Sons, Chichester, UK, 1988

[20] Ryan C G. Quantitative Trace Element Imaging Using PIXE and the Nuclear Microprobe. John Wiley & Sons, North Ryde, Australia, 2001

[21] Ryan C G, Cousens D R, Sie S H, Griffin W L, Suter G F, Clayton E. Quantitative pixe microanalysis of geological matemal using the CSIRO proton microprobe. Nucl. Instru. Meth. Phy. Res. B. 1990; 47:55-71. DOI: 10.1016/0168-583X(90)90047-X

[22] Yano J, Yachandra VK. X-ray absorption spectroscopy. Photosynthesis research. 2009;102(2-3):241. DOI: 10.1007/s11120-009-9473-8

[23] Błachucki W, Czapla-Masztafiak J, Sá J, Szlachetko J. A laboratorybased double X-ray spectrometer for simultaneous X-ray emission and X-ray absorption studies. Journal of Analytical Atomic Spectrometry. 2019;34(7):1409- 1415. DOI: 10.1039/C9JA00159J

[24] Koningsberger DC, Prins R. X-ray absorption: principles, applications, techniques of EXAFS, SEXAFS, and XANES. United States: John Wiley and Sons. 1988

[25] Penner-Hahn JE. X-ray absorption spectroscopy. e LS. 2001. DOI: 10.1038/ npg.els.0002984

[26] Al-Ebraheem A, Goettlicher J, Geraki K, Ralph S, Farquharson MJ. The determination of zinc, copper and iron oxidation state in invasive ductal carcinoma of breast tissue and normal surrounding tissue using XANES. X-Ray Spectrometry. 2010;39(5):332-337. DOI: 10.1002/xrs.1272

[27] Geraki K, Farquharson MJ, Bradley DA. Concentrations of Fe, Cu and Zn in breast tissue: a synchrotron XRF study. Physics in Medicine & Biology. 2002;47(13):2327-2339. DOI: 10.1088/0031-9155/47/13/310

[28] Geraki K, Farquharson MJ, Bradley DA. X-ray fluorescence and energy dispersive x-ray diffraction for the quantification of elemental concentrations in breast tissue. Physics in Medicine & Biology. 2003;49(1):99- 110. DOI: 10.1088/0031-9155/49/1/007

[29] Geraki K, Farquharson MJ, Bradley DA, Hugtenburg RP. A synchrotron XRF study on trace elements and potassium in breast tissue. Nuclear Instruments and Methods in Physics Research Section B: Beam Interactions with Materials and Atoms. 2004;213:564-568. DOI: 10.1016/ S0168-583X(03)01672-0

**26**

sab.2006.06.002

*Trace Elements and Their Effects on Human Health and Diseases*

[8] Benninghoff L, Czarnowski D V, Denkhaus E, Lemke K. Analysis of human tissues by total reflection X-ray fluorescence. Application of chemometrices for diagnostic cancer recognition. Spec. Acta Part B. 1997; 52:1039-1046. DOI: 10.1016/

S0584-8547(96)01626-6

[9] Hernandez-Caraballo E A, Marco-Parra L M. Direct analysis of blood serum by total reflection X-ray fluorescence spectrometry and application of an artificial neutral network approach for cancer diagnosis. Spec. Acta Part B. 2003; 58:2195-2201.

DOI: 10.1016/j.sab.2003.07.003

10.1017/CBO9780511470806

[11] Jenkins R, Gould R W, Gedcke D. Quantitative X-ray spectrometry. CRC Press; 1995. DOI:

10.1201/9781482273380

s00216-003-1765-9

[14] Cesareo R, Castellano A,

Buccolieri G, Quarta S, Marabelli M, Santopadre P, Leole M, Brunetti A, Portable equipment for energy dispersive X-ray fluorescence analysis of Giotto's frescoes in the Chapel of the Scrovegni, Nucl. Instrum. Methods

[12] Stand-zenieks P, Selin E. Background reduction of X-ray fluorescence spectra in a secondary target energy dispersive spectrometer. Nucl. Inst. Methods Phys. Res., B Beam Interact. Mater. Atoms. 1979; 165: 63-70. DOI: 10.1016/0029-554X(79)90308-2

[13] Custódio P, Carvalho M L, Nunes F, Trace elements determination by energy dispersive X-ray fluorescence (EDXRF) in human placenta and membrane: A comparative study. Anal. Bional. Chem. 2003; 375:1101-1106. DOI: 10.1007/

[10] Dyson N. X-rays in Atomic and Nuclear Physics. 2nd ed. Cambridge: Cambridge University Press; 1990. DOI:

[1] Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA: a cancer journal for clinicians. 2018;68(6):394-424. DOI:

10.3322/caac.21492

**References**

[2] Brinton LA, Gaudet MM, Gierach GL. Breast cancer. In: Thun MJ, Linet MS, Cerhan JR, Haiman CA, Schottenfeld D, editors. Cancer Epidemiology and Prevention. 4th ed. New York: Oxford University Press;2018. p. 861-888. DOI: 10.1093/ oso/9780190238667.001.0001

[3] Liou G-Y, Storz P. Reactive oxygen species in cancer. Free Radical Research. 2010; 44(5):1-31*.* DOI: 10.3109/10715761003667554

[4] Reddy S, Charles M, Naga Raju G, Byreddy S, Reddy T, Lakshmi P, Vijayan, V. Trace Elemental Analysis of Cancer-Afflicted Intestine by PIXE Technique. Biological trace element research. 2004; 102:265-282. DOI: 10.1385/bter:102:1-3:265

[5] Czarnowski D V, Denkhaus E, Lemke K. Determination of trace element distribution in cancerous and normal human tissues by total X-ray fluorescence analysis. Spec. Acta B. 1997; 52(7):1047-1052. DOI: 10.1016/

[6] Milde D, Altmannová K, Vysloužil K, Stužka V. Trace Element Levels in Blood Serum and Colon Tissue in Colorectal Cancer. Chemical Papers. 2005; 59(3):

[7] Magalhães T, Bohlen A V, Carvalho M L, Becker M. Trace elements in human cancerous and healthy tissues from the same individual: A comparative study by TXRF and EDXRF. Spec. Acta Part B. 2006; 61:1185-1193. DOI: 10.1016/j.

S0584-8547(96)01625-4

157-160. Corpus ID: 17410947

[30] Silva MP, Tomal A, Perez CA, Ribeiro-Silva A, Poletti ME. Determination of Ca, Fe, Cu and Zn and their correlations in breast cancer and normal adjacent tissues. X-Ray Spectrometry: An International Journal. 2009;38(2):103-111. DOI: 10.1002/ xrs.1126

[31] Magalhaes T, Becker M, Carvalho ML, Von Bohlen A. Study of Br, Zn, Cu and Fe concentrations in healthy and cancer breast tissues by TXRF. Spectrochimica Acta Part B: Atomic Spectroscopy. 2008;63(12):1473- 1479. DOI: 10.1016/j.sab.2008.10.014

[32] Singh R, Kainth HS, Prasher P, Singh T. Trace elemental analysis of human breast cancerous blood by advanced PC-WDXRF technique. Nuclear Instruments and Methods in Physics Research Section B: Beam Interactions with Materials and Atoms. 2018;419:44-48. DOI: 10.1016/j. nimb.2018.01.029

[33] Naidu BG, Sarita P, Raju GN, Tiwari MK. Multivariate analysis of trace elemental data obtained from blood serum of breast cancer patients using SRXRF. Results in Physics. 2019;12:673-680. DOI: 10.1016/j. rinp.2018.12.020

[34] Sarita P, Naga Raju G, Pradeep A, Rautray T, Seetharami Reddy B, Bhuloka Reddy S, Vijayan V. Analysis of trace elements in blood sera of breast cancer patients by particle induced X-ray emission. Journal of Radioanalytical and Nuclear Chemistry. 2012;294(3):355- 361. DOI: 10.1007/s10967-011-1505-0

[35] Kwang-Hoong N G, Bradley D A, Lai-Meng L, Elevated trace element concentrations in malignant breast tissues. The Br. J. Radiol. 1997;70:375- 382. 10.1259/bjr.70.832.9166074

[36] Kuo H W, Chen S F, Wu C C, Chen D R, Lee J H. Serum and tissue trace elements in patients with breast cancer in Taiwan. Biol. Trace Elem. Res. 2002; 89 (1): 1-11. DOI: 10.1385/BTER:89:1:1

[37] Naga Raju G, Sarita P, Kumar M R, G.A.V.R. Murty, Reddy B S, Lakshminarayana S, Vijayan V, Lakshmi P V B R, Gavarasan S, S.B. Reddy. Trace elemental correlation study in malignant and normal breast tissue by PIXE technique. Nucl. Inst. and Meth. In Phys. Res. B 2006;247 (2): 361-367.

[38] Magalhães T, Carvalho ML, Von Bohlen A, Becker M. Study on trace elements behaviour in cancerous and healthy tissues of colon, breast and stomach: Total reflection X-ray fluorescence applications. Spectrochimica Acta Part B: Atomic Spectroscopy. 2010;65(6):493-498. DOI: 10.1016/j.sab.2010.04.001

[39] Kabiri Z, Kakuee O, Fathollahi V, Stout B. Trace element abnormalities in the scalp hair of breast cancer patients. International Journal of PIXE. 2014;24(01n02):49-58. DOI: 10.1142/ S0129083514500065

[40] Weinberg ED. The role of iron in cancer. European journal of cancer prevention: the official journal of the European Cancer Prevention Organisation (ECP). 1996;5(1):19-36. PMID: 8664805

[41] Toyokuni S. Role of iron in carcinogenesis: cancer as a ferrotoxic disease. Cancer science. 2009;100(1):9-16. DOI: 10.1111/j.1349-7006.2008.01001.x

[42] Schwartz M K. Role of trace elements in cancer. Cancer Res. 35 (11 Pt.2) (1975) 3481-3487. PMID: 1104155

[43] Sky-Peck H H. Trace metals and Neoplasia. Clin. Physiol. Biochem. 1986; 4:99-111. PMID: 3514058

**29**

*Role of Trace Elements in Breast Cancer and Their Characterization Using X-Ray Fluorescence…*

jcb.22049

Journal of cellular biochemistry. 2009;106(5):750-757. DOI: 10.1002/

DOI: 10.3390/ijms18112285

[53] Takatani-Nakase T. Zinc transporters and the progression of breast cancers. Biological and Pharmaceutical Bulletin.

DOI: 10.3390/nu4070648

bpb.b18-00086

2018;41(10):1517-1522. DOI: 10.1248/

[54] Grattan BJ, Freake HC. Zinc and cancer: implications for LIV-1 in breast cancer. Nutrients. 2012;4(7):648-675.

[55] Sugiyama M. Role of physiological antioxidants in chromium (VI)-induced cellular injury. Free Radical Biology and Medicine. 1992;12(5):397-407. 10.1016/0891-5849(92)90089-y

[56] Raaschou-Nielsen O, Pavuk M, LeBlanc A, Dumas P, Weber JP, Olsen A, Tjønnland A, Overvad K, Olsen JH. Adipose organochlorine concentrations

and risk of breast cancer among postmenopausal Danish women. Cancer Epidemiology and Prevention Biomarkers. 2005;14(1):67-74. PMID:

[57] Vineis P, D'Amore F, Working Group on the Epidemiology of Hematolymphopoietic Malignancies in Italy. The role of occupational exposure and immunodeficiency in B-cell malignancies. Epidemiology. 1992:266-270. http://www.jstor.org/

[58] Calaf GM, Ponce-Cusi R, Aguayo F, Muñoz JP, Bleak TC. Endocrine disruptors from the environment affecting breast cancer. Oncology Letters. 2020 Jul 1;20(1):19- 32. DOI: 10.3892/ol.2020.11566

15668478

stable/3703163

[52] Maret W. Zinc in cellular regulation: The nature and significance of "zinc signals". International Journal of Molecular Sciences. 2017;18(11):2285.

*DOI: http://dx.doi.org/10.5772/intechopen.95491*

observations in patients with malignant lymphoma. Cancer. 1973;32(6):1512-

Biological Systems: Carcinogenicity and Metal Ions, Marcel Dekker, Inc.: New

AID-CNCR2820320631>3.0.CO;2-P

[45] (Ed.: H. Sigel), Metal ions in

[46] Quintero-Fabián S, Arreola R, Becerril-Villanueva E, Torres-Romero JC, Arana-Argáez VE,

Lara-Riegos J, Ramírez-Camacho MA, Alvarez Sanchez ME. Role of matrix metalloproteinases in angiogenesis and cancer. Frontiers in oncology. 2019;9:1370. DOI: 10.3389/

[47] Mulware SJ. Comparative trace elemental analysis in cancerous and noncancerous human tissues using PIXE. Journal of biophysics. 2013;2013.

[48] Carvalho ML, Magalhães T,

Becker M, Von Bohlen A. Trace elements in human cancerous and healthy tissues: A comparative study by EDXRF, TXRF, synchrotron radiation and PIXE. Spectrochimica Acta Part B: Atomic Spectroscopy. 2007;62(9):1004-1011. DOI: 10.1016/j.sab.2007.03.030

[49] Kew M C, Mallett R C. Hepatic zinc concentrations in primary cancer of the liver. Brit. J. Cancer. 1974; 29 (1): 80-83.

[50] Lee R, Woo W, Wu B, Kummer A, Duminy H, Xu Z. Zinc accumulation in N-methyl-N-nitrosourea-induced rat mammary tumors is accompanied by an altered expression of ZnT-1 and metallothionein. Experimental Biology and Medicine. 2003;228(6):689-696.

[51] Franklin RB, Costello LC. The important role of the apoptotic effects of zinc in the development of cancers.

1524. DOI: 10.1002/1097- 0142(197312)32:6<1512::

York, 1980.

fonc.2019.01370

10.1155/2013/192026

10.1038/bjc.1974.11

PMID: 12773700

[44] Hrgovcic M, Tessmer CF, Thomas FB, Ong PS, Gamble JF, Shullenberger CC. Serum copper *Role of Trace Elements in Breast Cancer and Their Characterization Using X-Ray Fluorescence… DOI: http://dx.doi.org/10.5772/intechopen.95491*

observations in patients with malignant lymphoma. Cancer. 1973;32(6):1512- 1524. DOI: 10.1002/1097- 0142(197312)32:6<1512:: AID-CNCR2820320631>3.0.CO;2-P

*Trace Elements and Their Effects on Human Health and Diseases*

in Taiwan. Biol. Trace Elem. Res. 2002; 89 (1): 1-11. DOI: 10.1385/BTER:89:1:1

[37] Naga Raju G, Sarita P, Kumar M R, G.A.V.R. Murty, Reddy B S, Lakshminarayana S, Vijayan V, Lakshmi P V B R, Gavarasan S, S.B. Reddy. Trace elemental correlation study in malignant and normal breast tissue by PIXE technique. Nucl. Inst. and Meth. In Phys. Res. B 2006;247 (2): 361-367.

[38] Magalhães T, Carvalho ML, Von Bohlen A, Becker M. Study on trace elements behaviour in cancerous and healthy tissues of colon, breast and stomach: Total reflection X-ray fluorescence applications. Spectrochimica Acta Part B: Atomic Spectroscopy. 2010;65(6):493-498. DOI:

[39] Kabiri Z, Kakuee O, Fathollahi V, Stout B. Trace element abnormalities in the scalp hair of breast cancer patients. International Journal of PIXE. 2014;24(01n02):49-58. DOI: 10.1142/

[40] Weinberg ED. The role of iron in cancer. European journal of cancer prevention: the official journal of the European Cancer Prevention Organisation (ECP). 1996;5(1):19-36.

10.1016/j.sab.2010.04.001

S0129083514500065

PMID: 8664805

[41] Toyokuni S. Role of iron in carcinogenesis: cancer as a ferrotoxic disease. Cancer science. 2009;100(1):9-16. DOI: 10.1111/j.1349-7006.2008.01001.x

[42] Schwartz M K. Role of trace elements in cancer. Cancer Res. 35 (11 Pt.2) (1975) 3481-3487. PMID: 1104155

[43] Sky-Peck H H. Trace metals and Neoplasia. Clin. Physiol. Biochem. 1986;

4:99-111. PMID: 3514058

[44] Hrgovcic M, Tessmer CF, Thomas FB, Ong PS, Gamble JF, Shullenberger CC. Serum copper

[30] Silva MP, Tomal A, Perez CA, Ribeiro-Silva A, Poletti ME.

[31] Magalhaes T, Becker M,

xrs.1126

Determination of Ca, Fe, Cu and Zn and their correlations in breast cancer and normal adjacent tissues. X-Ray Spectrometry: An International Journal. 2009;38(2):103-111. DOI: 10.1002/

Carvalho ML, Von Bohlen A. Study of Br, Zn, Cu and Fe concentrations in healthy and cancer breast tissues by TXRF. Spectrochimica Acta Part B: Atomic Spectroscopy. 2008;63(12):1473- 1479. DOI: 10.1016/j.sab.2008.10.014

[32] Singh R, Kainth HS, Prasher P, Singh T. Trace elemental analysis of human breast cancerous blood by advanced PC-WDXRF technique. Nuclear Instruments and Methods in Physics Research Section B: Beam Interactions with Materials and Atoms.

2018;419:44-48. DOI: 10.1016/j.

[33] Naidu BG, Sarita P, Raju GN, Tiwari MK. Multivariate analysis of trace elemental data obtained from blood serum of breast cancer patients using SRXRF. Results in Physics. 2019;12:673-680. DOI: 10.1016/j.

[34] Sarita P, Naga Raju G, Pradeep A, Rautray T, Seetharami Reddy B, Bhuloka Reddy S, Vijayan V. Analysis of trace elements in blood sera of breast cancer patients by particle induced X-ray emission. Journal of Radioanalytical and Nuclear Chemistry. 2012;294(3):355- 361. DOI: 10.1007/s10967-011-1505-0

[35] Kwang-Hoong N G, Bradley D A, Lai-Meng L, Elevated trace element concentrations in malignant breast tissues. The Br. J. Radiol. 1997;70:375- 382. 10.1259/bjr.70.832.9166074

[36] Kuo H W, Chen S F, Wu C C, Chen D R, Lee J H. Serum and tissue trace elements in patients with breast cancer

nimb.2018.01.029

rinp.2018.12.020

**28**

[45] (Ed.: H. Sigel), Metal ions in Biological Systems: Carcinogenicity and Metal Ions, Marcel Dekker, Inc.: New York, 1980.

[46] Quintero-Fabián S, Arreola R, Becerril-Villanueva E, Torres-Romero JC, Arana-Argáez VE, Lara-Riegos J, Ramírez-Camacho MA, Alvarez Sanchez ME. Role of matrix metalloproteinases in angiogenesis and cancer. Frontiers in oncology. 2019;9:1370. DOI: 10.3389/ fonc.2019.01370

[47] Mulware SJ. Comparative trace elemental analysis in cancerous and noncancerous human tissues using PIXE. Journal of biophysics. 2013;2013. 10.1155/2013/192026

[48] Carvalho ML, Magalhães T, Becker M, Von Bohlen A. Trace elements in human cancerous and healthy tissues: A comparative study by EDXRF, TXRF, synchrotron radiation and PIXE. Spectrochimica Acta Part B: Atomic Spectroscopy. 2007;62(9):1004-1011. DOI: 10.1016/j.sab.2007.03.030

[49] Kew M C, Mallett R C. Hepatic zinc concentrations in primary cancer of the liver. Brit. J. Cancer. 1974; 29 (1): 80-83. 10.1038/bjc.1974.11

[50] Lee R, Woo W, Wu B, Kummer A, Duminy H, Xu Z. Zinc accumulation in N-methyl-N-nitrosourea-induced rat mammary tumors is accompanied by an altered expression of ZnT-1 and metallothionein. Experimental Biology and Medicine. 2003;228(6):689-696. PMID: 12773700

[51] Franklin RB, Costello LC. The important role of the apoptotic effects of zinc in the development of cancers. Journal of cellular biochemistry. 2009;106(5):750-757. DOI: 10.1002/ jcb.22049

[52] Maret W. Zinc in cellular regulation: The nature and significance of "zinc signals". International Journal of Molecular Sciences. 2017;18(11):2285. DOI: 10.3390/ijms18112285

[53] Takatani-Nakase T. Zinc transporters and the progression of breast cancers. Biological and Pharmaceutical Bulletin. 2018;41(10):1517-1522. DOI: 10.1248/ bpb.b18-00086

[54] Grattan BJ, Freake HC. Zinc and cancer: implications for LIV-1 in breast cancer. Nutrients. 2012;4(7):648-675. DOI: 10.3390/nu4070648

[55] Sugiyama M. Role of physiological antioxidants in chromium (VI)-induced cellular injury. Free Radical Biology and Medicine. 1992;12(5):397-407. 10.1016/0891-5849(92)90089-y

[56] Raaschou-Nielsen O, Pavuk M, LeBlanc A, Dumas P, Weber JP, Olsen A, Tjønnland A, Overvad K, Olsen JH. Adipose organochlorine concentrations and risk of breast cancer among postmenopausal Danish women. Cancer Epidemiology and Prevention Biomarkers. 2005;14(1):67-74. PMID: 15668478

[57] Vineis P, D'Amore F, Working Group on the Epidemiology of Hematolymphopoietic Malignancies in Italy. The role of occupational exposure and immunodeficiency in B-cell malignancies. Epidemiology. 1992:266-270. http://www.jstor.org/ stable/3703163

[58] Calaf GM, Ponce-Cusi R, Aguayo F, Muñoz JP, Bleak TC. Endocrine disruptors from the environment affecting breast cancer. Oncology Letters. 2020 Jul 1;20(1):19- 32. DOI: 10.3892/ol.2020.11566

[59] Rizk SL, Sky-Peck HH. Comparison between concentrations of trace elements in normal and neoplastic human breast tissue. Cancer research. 1984;44(11):5390-5394. PMID: 6488192

[60] Cui Y, Rohan TE. Vitamin D, calcium, and breast cancer risk: a review. Cancer Epidemiology and Prevention Biomarkers. 2006;15(8):1427-1437. DOI: 10.1158/1055-9965.EPI-06-0075

[61] Hidayat K, Chen GC, Zhang R, Du X, Zou SY, Shi BM, Qin LQ. Calcium intake and breast cancer risk: meta-analysis of prospective cohort studies. British Journal of Nutrition. 2016;116(1):158-166. DOI: 10.1017/ S0007114516001768

[62] Hilborn DA. Serum stimulation of phosphate uptake into 3T3 cells. Journal of cellular physiology. 1976;87(1):111- 121. DOI: 10.1002/jcp.1040870114

[63] Rubin H, Sanui H. Complexes of inorganic pyrophosphate, orthophosphate, and calcium as stimulants of 3T3 cell multiplication. Proceedings of the National Academy of Sciences USA. 1977;74(11):5026-5030. DOI: 10.1073/pnas.74.11.5026

[64] Abotaleb M, Kubatka P, Caprnda M, Varghese E, Zolakova B, Zubor P, Opatrilova R, Kruzliak P, Stefanicka P, Büsselberg D. Chemotherapeutic agents for the treatment of metastatic breast cancer: An update. Biomedicine & Pharmacotherapy. 2018;101:458-477. DOI: 10.1016/j.biopha.2018.02.108

[65] Lim EJ, Hong DY, Park JH, Joung YH, Darvin P, Kim SY, Na YM, Hwang TS, Ye SK, Moon ES, Cho BW. Methylsulfonylmethane suppresses breast cancer growth by downregulating STAT3 and STAT5b pathways. PloS one. 2012;7(4):e33361. DOI: 10.1371/journal.pone.0033361

[66] Wang Z. Roles of K+ channels in regulating tumour cell proliferation and apoptosis. Pflügers Archiv. 2004;448(3):274-286. DOI: 10.1007/ s00424-004-1258-5

[67] Frajese GV, Benvenuto M, Fantini M, Ambrosin E, Sacchetti P, Masuelli L, Giganti MG, Modesti A, Bei R. Potassium increases the antitumor effects of ascorbic acid in breast cancer cell lines in vitro. Oncology letters. 2016;11(6):4224-4234. DOI: 10.3892/ol.2016.4506

[68] Chen JQ, Contreras RG, Wang R, Fernandez SV, Shoshani L, Russo IH, Cereijido M, Russo J. Sodium/potasium ATPase (Na+, K+-ATPase) and ouabain/ related cardiac glycosides: a new paradigm for development of antibreast cancer drugs?. Breast cancer research and treatment. 2006; 96(1):1- 15. DOI: 10.1007/s10549-005-9053-3

[69] Robey IF, Baggett BK, Kirkpatrick ND, Roe DJ, Dosescu J, Sloane BF, Hashim AI, Morse DL, Raghunand N, Gatenby RA, Gillies RJ. Bicarbonate increases tumor pH and inhibits spontaneous metastases. Cancer research. 2009;69(6):2260-2268. DOI: 10.1158/0008-5472.CAN-07-5575

[70] Anastassopoulou J, Theophanides T. Magnesium–DNA interactions and the possible relation of magnesium to carcinogenesis. Irradiation and free radicals. Critical reviews in oncology/ hematology. 2002;42(1):79-91. DOI: 10.1016/S1040-8428(02)00006-9

[71] Wolf FI, Cittadini AR, Maier JA. Magnesium and tumors: ally or foe?. Cancer treatment reviews. 2009;35(4):378-382. DOI: 10.1016/j. ctrv.2009.01.003

[72] Mendes PM, Bezerra DL, dos Santos LR, de Oliveira Santos R, de Sousa Melo SR, Morais JB, Severo JS, Vieira SC, do Nascimento Marreiro D.

**31**

*Role of Trace Elements in Breast Cancer and Their Characterization Using X-Ray Fluorescence…*

Synthesis and antiproliferative activity of novel symmetrical alkylthio-and alkylseleno-imidocarbamates. European

journal of medicinal chemistry. 2011;1;46(1):265-74. DOI: 10.1016/j.

[80] Combs Jr GF, Clark LC,

Turnbull BW. An analysis of cancer prevention by selenium. Biofactors. 2001;14(1-4):153-159. DOI: 10.1002/

[81] Ruiz-Ramos R, Lopez-Carrillo L, Rios-Perez AD, De Vizcaya-Ruíz A, Cebrian ME. Sodium arsenite induces ROS generation, DNA oxidative damage, HO-1 and c-Myc proteins, NF-κB activation and cell proliferation in human breast cancer MCF-7 cells. Mutation Research/Genetic Toxicology and Environmental Mutagenesis. 2009;674(1-2):109-115. DOI: 10.1016/j.

[82] Wang Y, Zhang Y, Yang L, Cai B, Li J, Zhou Y, Yin L, Yang L, Yang B, Lu Y. Arsenic trioxide induces the apoptosis of human breast cancer MCF-7 cells through activation of caspase-3 and inhibition of HERG channels. Experimental and therapeutic medicine.

2011;2(3):481-486. DOI: 10.3892/

[83] Fuster D, Herranz R, Vidal-Sicart S, Munoz M, Conill C, Mateos JJ, Martin F, Pons F. Usefulness of strontium-89 for bone pain palliation in metastatic breast cancer patients. Nuclear medicine communications. 2000;21(7):623-626.

ejmech.2010.11.013

biof.5520140120

mrgentox.2008.09.021

etm.2011.224

*DOI: http://dx.doi.org/10.5772/intechopen.95491*

Magnesium in breast Cancer: what is its influence on the progression of this disease?. Biological trace element research. 2018;184(2):334-339. DOI:

[73] Huang WQ, Long WQ, Mo XF,

Huang J, Zhang CX. Direct and indirect

magnesium intake and breast cancer risk. Scientific Reports. 2019;9(1):1-10. DOI: 10.1038/s41598-019-42282-y

[74] Atoe K, Idemudia O, Eboreime O. Serum magnesium levels in women with breast cancer in Benin City, Nigeria. International journal of tropical diseases and health. 2014;4(6):723-728. DOI:

10.1007/s12011-017-1207-8

Zhang NQ, Luo H, Lin FY,

10.9734/IJTDH/2014/5041

10.1016/j.mehy.2010.02.037

10.1007/PL00000668

DOI: 10.1002/jso.2930150111.

[78] Li Z, Carrier L, Belame A,

[79] Ibáñez E, Plano D, Font M,

Calvo A, Prior C, Palop JA, Sanmartín C.

Rowan BG. Combination of

[75] Sahmoun AE, Singh BB. Does a higher ratio of serum calcium to magnesium increase the risk for

postmenopausal breast cancer?. Medical hypotheses. 2010;75(3):315-318. DOI:

[76] Schrauzer GN. Anticarcinogenic effects of selenium. Cellular and Molecular Life Sciences CMLS. 2000 Dec 1;57(13-14):1864-1873. DOI:

[77] McConnell KP, Jager RM, Bland KI, Blotcky AJ. The relationship of dietary selenium and breast cancer. Journal of Surgical Oncology. 1980;15(1):67-70.

Thiyagarajah A, Salvo VA, Burow ME,

methylselenocysteine with tamoxifen inhibits MCF-7 breast cancer xenografts in nude mice through elevated apoptosis and reduced angiogenesis. Breast cancer research and treatment. 2009;118(1):33- 43. DOI: 10.1007/s10549-008-0216-x

associations between dietary

*Role of Trace Elements in Breast Cancer and Their Characterization Using X-Ray Fluorescence… DOI: http://dx.doi.org/10.5772/intechopen.95491*

Magnesium in breast Cancer: what is its influence on the progression of this disease?. Biological trace element research. 2018;184(2):334-339. DOI: 10.1007/s12011-017-1207-8

*Trace Elements and Their Effects on Human Health and Diseases*

[66] Wang Z. Roles of K+ channels in regulating tumour cell proliferation and apoptosis. Pflügers Archiv. 2004;448(3):274-286. DOI: 10.1007/

s00424-004-1258-5

[67] Frajese GV, Benvenuto M, Fantini M, Ambrosin E, Sacchetti P, Masuelli L, Giganti MG, Modesti A, Bei R. Potassium increases the antitumor effects of ascorbic acid in breast cancer cell lines in vitro. Oncology letters. 2016;11(6):4224-4234.

DOI: 10.3892/ol.2016.4506

[68] Chen JQ, Contreras RG, Wang R, Fernandez SV, Shoshani L, Russo IH, Cereijido M, Russo J. Sodium/potasium ATPase (Na+, K+-ATPase) and ouabain/

related cardiac glycosides: a new paradigm for development of antibreast cancer drugs?. Breast cancer research and treatment. 2006; 96(1):1- 15. DOI: 10.1007/s10549-005-9053-3

[69] Robey IF, Baggett BK,

Kirkpatrick ND, Roe DJ, Dosescu J, Sloane BF, Hashim AI, Morse DL, Raghunand N, Gatenby RA, Gillies RJ. Bicarbonate increases tumor pH and inhibits spontaneous metastases. Cancer research. 2009;69(6):2260-2268. DOI: 10.1158/0008-5472.CAN-07-5575

[70] Anastassopoulou J, Theophanides T. Magnesium–DNA interactions and the possible relation of magnesium to carcinogenesis. Irradiation and free radicals. Critical reviews in oncology/ hematology. 2002;42(1):79-91. DOI: 10.1016/S1040-8428(02)00006-9

[71] Wolf FI, Cittadini AR, Maier JA. Magnesium and tumors: ally or foe?. Cancer treatment reviews. 2009;35(4):378-382. DOI: 10.1016/j.

[72] Mendes PM, Bezerra DL, dos Santos LR, de Oliveira Santos R, de Sousa Melo SR, Morais JB, Severo JS, Vieira SC, do Nascimento Marreiro D.

ctrv.2009.01.003

[59] Rizk SL, Sky-Peck HH. Comparison

Vitamin D, calcium, and breast cancer risk: a review. Cancer Epidemiology

[61] Hidayat K, Chen GC, Zhang R, Du X, Zou SY, Shi BM, Qin LQ. Calcium

[62] Hilborn DA. Serum stimulation of phosphate uptake into 3T3 cells. Journal of cellular physiology. 1976;87(1):111- 121. DOI: 10.1002/jcp.1040870114

[63] Rubin H, Sanui H. Complexes of inorganic pyrophosphate, orthophosphate, and calcium as stimulants of 3T3 cell multiplication. Proceedings of the National Academy of Sciences USA. 1977;74(11):5026-5030.

DOI: 10.1073/pnas.74.11.5026

[64] Abotaleb M, Kubatka P, Caprnda M, Varghese E,

An update. Biomedicine &

[65] Lim EJ, Hong DY, Park JH, Joung YH, Darvin P, Kim SY, Na YM, Hwang TS, Ye SK, Moon ES, Cho BW. Methylsulfonylmethane suppresses breast cancer growth by down-

Zolakova B, Zubor P, Opatrilova R, Kruzliak P, Stefanicka P, Büsselberg D. Chemotherapeutic agents for the treatment of metastatic breast cancer:

Pharmacotherapy. 2018;101:458-477. DOI: 10.1016/j.biopha.2018.02.108

regulating STAT3 and STAT5b pathways.

PloS one. 2012;7(4):e33361. DOI: 10.1371/journal.pone.0033361

between concentrations of trace elements in normal and neoplastic human breast tissue. Cancer research. 1984;44(11):5390-5394. PMID: 6488192

[60] Cui Y, Rohan TE.

and Prevention Biomarkers. 2006;15(8):1427-1437. DOI: 10.1158/1055-9965.EPI-06-0075

intake and breast cancer risk: meta-analysis of prospective cohort studies. British Journal of Nutrition. 2016;116(1):158-166. DOI: 10.1017/

S0007114516001768

**30**

[73] Huang WQ, Long WQ, Mo XF, Zhang NQ, Luo H, Lin FY, Huang J, Zhang CX. Direct and indirect associations between dietary magnesium intake and breast cancer risk. Scientific Reports. 2019;9(1):1-10. DOI: 10.1038/s41598-019-42282-y

[74] Atoe K, Idemudia O, Eboreime O. Serum magnesium levels in women with breast cancer in Benin City, Nigeria. International journal of tropical diseases and health. 2014;4(6):723-728. DOI: 10.9734/IJTDH/2014/5041

[75] Sahmoun AE, Singh BB. Does a higher ratio of serum calcium to magnesium increase the risk for postmenopausal breast cancer?. Medical hypotheses. 2010;75(3):315-318. DOI: 10.1016/j.mehy.2010.02.037

[76] Schrauzer GN. Anticarcinogenic effects of selenium. Cellular and Molecular Life Sciences CMLS. 2000 Dec 1;57(13-14):1864-1873. DOI: 10.1007/PL00000668

[77] McConnell KP, Jager RM, Bland KI, Blotcky AJ. The relationship of dietary selenium and breast cancer. Journal of Surgical Oncology. 1980;15(1):67-70. DOI: 10.1002/jso.2930150111.

[78] Li Z, Carrier L, Belame A, Thiyagarajah A, Salvo VA, Burow ME, Rowan BG. Combination of methylselenocysteine with tamoxifen inhibits MCF-7 breast cancer xenografts in nude mice through elevated apoptosis and reduced angiogenesis. Breast cancer research and treatment. 2009;118(1):33- 43. DOI: 10.1007/s10549-008-0216-x

[79] Ibáñez E, Plano D, Font M, Calvo A, Prior C, Palop JA, Sanmartín C. Synthesis and antiproliferative activity of novel symmetrical alkylthio-and alkylseleno-imidocarbamates. European journal of medicinal chemistry. 2011;1;46(1):265-74. DOI: 10.1016/j. ejmech.2010.11.013

[80] Combs Jr GF, Clark LC, Turnbull BW. An analysis of cancer prevention by selenium. Biofactors. 2001;14(1-4):153-159. DOI: 10.1002/ biof.5520140120

[81] Ruiz-Ramos R, Lopez-Carrillo L, Rios-Perez AD, De Vizcaya-Ruíz A, Cebrian ME. Sodium arsenite induces ROS generation, DNA oxidative damage, HO-1 and c-Myc proteins, NF-κB activation and cell proliferation in human breast cancer MCF-7 cells. Mutation Research/Genetic Toxicology and Environmental Mutagenesis. 2009;674(1-2):109-115. DOI: 10.1016/j. mrgentox.2008.09.021

[82] Wang Y, Zhang Y, Yang L, Cai B, Li J, Zhou Y, Yin L, Yang L, Yang B, Lu Y. Arsenic trioxide induces the apoptosis of human breast cancer MCF-7 cells through activation of caspase-3 and inhibition of HERG channels. Experimental and therapeutic medicine. 2011;2(3):481-486. DOI: 10.3892/ etm.2011.224

[83] Fuster D, Herranz R, Vidal-Sicart S, Munoz M, Conill C, Mateos JJ, Martin F, Pons F. Usefulness of strontium-89 for bone pain palliation in metastatic breast cancer patients. Nuclear medicine communications. 2000;21(7):623-626.

**33**

**Chapter 3**

Joint

**Abstract**

**1. Introduction**

Analysis of Occurrence of

Elements in Tissues of the Knee

The mineral structure of bones is never static, it is a living structure, reacting and adapting to load and having the ability to remodel. Skeletal cells work continuously to maintain the remodelling process therefore they are in a constant state of dynamic balance both in the sense of composition and structure, and they react to external mechanical forces. The remodelling processes that occur in the bone tissue allow for a proper functioning of this tissue, as well as for inclusion of additional elements, toxic ones included, in the remodelled bone, and they affect the metabolic processes occurring therein. This may result in disturbances in the osteoarticular system, manifested by changes in the bone tissue and within other organs. The influence of tobacco smoking on the content of strontium, lead, calcium, phosphorus, sodium and magnesium has not been confirmed. Non-smokers showed a high iron content in knee joint tissues compared to smokers. There were no statistically significant differences in the content of cadmium, nickel, copper and zinc in women and men in the studied knee joint components. With age, an increase in the content of chromium in knee joint tissues was observed, while gender, place of

**Keywords:** knee joint tissues, structural and trace elements, environmental hazards

Many joints can be distinguished in the human body, but one of them stands out in terms of function and size. It is the knee joint [1]. It belongs to a group of complex joints and connects the femur and the tibia together. This largest joint, apart from the mentioned elements, is formed by the sesamoid bone in the form of the kneecap, and two pieces of meniscus, which allow to match the joint surfaces to each other during movement. The knee joint allows making straightening and flexion movements, but also rotational movements possible only in incomplete joint flexion [2]. The entire structure of the knee joint is strengthened by strong internal and external ligaments. The afore-mentioned joint is the second most strained joint in the human body, after the ankle joint. Due to the powerful force that the quadriceps exerts on the kneecap (max. 300 kg), the knee joint is exposed to overload. Taking into account the functions of the knee joint, it must be both mobile and

*Wojciech Roczniak, Magdalena Babuśka Roczniak,* 

*Elżbieta Cipora and Barbara Brodziak Dopierała*

residence and occupational exposure had no effect.

flexible, as well as resistant to pressure [3, 4].

#### **Chapter 3**
