Tumor Suppressor Genes

## **Chapter 5**

## Cancer Genes and Breast Cancers

*Metin Budak and Hatice Segmen*

## **Abstract**

Cancer is the name given to all malignant tumors, the main reason for which is uncontrolled growth, and the tumor, which has become a mass as a result of uncontrolled cell proliferation, also attacks the surrounding cells and envelops the whole body (metastasis) in the later stages of the disease. Although cancer is an important health problem, it is not a common disease in childhood. On the other hand, statistics show that cancer affects one in three adults, causes up to 20% of all deaths, and covers about 10% of treatment costs in developed countries. Although it is known that cancer develops under the influence of genetic and environmental factors, environmental factors are more prominent in the formation of some types of cancer. Breast cancer is one of the cancer types known to have tumor suppressor genes in its etiology. These tumor suppressor genes are BRCA1 and BRCA2 genes. Studies have shown that these two genes are particularly effective in the development of familial breast cancers. These types of cancers occur much earlier than non-familial cancers. The research, two genes; It has shown that it is especially effective in the development of familial breast cancers.

**Keywords:** BRCA1, BRCA2, tumor suppressor, oncogenes, cancer

## **1. Introduction**

The term cancer is not the name of a single disease, but the name was given to all malignant tumors, the main reason for which is uncontrolled growth. The tumor, which becomes a mass as a result of uncontrolled cell proliferation, also attacks the surrounding cells and tends to spread throughout the body in the later stages of the disease (metastasis). Although cancer is an important health problem, it is not a common disease in childhood. On the other hand, statistics show that cancer affects one in three adults, causes up to 20% of all deaths, and covers about 10% of treatment costs in developed countries [1]. Cancer, which develops as a result of uncontrolled cell growth and development, is a phenomenon that occurs as a result of a complex series of cellular mechanisms working differently from normal. It is known that cancer occurs as a result of mutations in somatic cells and these mutations affect the expression of a series of genes. Cancers can develop in each tissue group depending on age, gender, and environmental factors [2–4]. Although it is known that cancer develops under the influence of genetic and environmental factors, environmental factors are more prominent in the formation of some types of cancer. It is now known to affect [5, 6]. There are two gene groups known to be involved in cancer formation. These are (1) Tumor suppressor genes and (2) proto-oncogenes [7, 8]. Breast cancers are the leading cancer types known to have tumor suppressor genes in their etiology. BRCA1 and BRCA2 genes are the leading tumor suppressor genes specific to breast cancers [9]. Studies have shown that these

#### **Figure 1.**

*Estimated age-standardized incidence and mortality rates (world) in 2020, worldwide, for both sexes, all ages [17].*

two genes are particularly effective in the development of familial breast cancers. While the majority of cancers are sporadic, a small percentage can be hereditary, that is, familial. While the first mutation in the genes involved in hereditary cancers is inherited familial, the fact that the second mutation occurs in a limited number of somatic cells after birth is sufficient for cancerization. These types of cancers occur much earlier than non-familial cancers [9–16]. According to World Health Organization; When cancer-related deaths in women were investigated between 2019 and 2020 worldwide, the most common type of cancer in all ages and genders is breast cancer, followed by prostate cancer and lung cancer, the least common cancer is thyroid cancer. However, the most common cause of death is lung cancer and breast cancer is the second most common type of cancer. According to International Agency for Research on Cancer of the World Health Organization; new cases and death rates of cancer the worldwide for 2020 are given below (**Figure 1**) [17–20], https://gco.iarc.fr/.

## **2. Causes of cancer**

Although a lot of important information about the etiology of cancer has been obtained in recent years, the molecular mechanisms that cause cancer formation, that is, the excessive proliferation of a normal cell out of control, are still not fully clarified, and a new mechanism may emerge every year and hereditary factors are known to play a role together. Environmental factors include some chemical agents (nicotine), nutrition, radiation, viruses, living environmental conditions, and lifestyle [16, 21, 22].

#### **2.1 Environmental factors**

#### *2.1.1 Chemical carcinogens*

There is a threshold value for many carcinogens, amounts that do not exceed this threshold value are harmless. One-third of cancers seen in the USA and Europe are cancers that develop due to the use of cigarettes and other tobacco products. Working conditions and some occupational chemicals are among the other environmental factors that cause cancer. It is known that chemical agents such as asbestos and nicotine cause cancer formation [23–26].

## *2.1.2 Physical carcinogens*

Ionizing Radiation. Skin cancers were common in the hands of radiologists in the periods when primitive devices were used and prevention methods were not well known. In studies conducted in the following years, it has been shown that bone, thyroid, lung, breast cancer, leukemia, and lymphoma develop with the effect of radiation [27–29]. Ultraviolet Rays (U.V). U.V rays have been shown to be associated with skin cancers. These include basal cell skin cancer, squamous (stratified squamous epithelium) skin cancer, and skin cancers such as melanoma [30–34].

## *2.1.3 Hereditary and genetic factors*

Although cancer is a genetic disease, very few cancer cases show hereditary characteristics. Among all cancer types, the rate of hereditary cancers is less than 1%. In families with hereditary cancer cases, cancer occurs more frequently than in the normal population. In families where cancer is inherited; The probability of passing the cancer gene from mother or father to child is 50%. Cancer cases in individuals in such families occur at an earlier age than in the general population. The tissues with the most familial cancer cases are colon, endometrium, ovary, and breast [35–37]. Two groups are very important in the formation of cancer. These; proto-oncogenes are tumor suppressor genes.

## *2.1.3.1 Proto-oncogenes and oncogenes*

It is known that proto-oncogenes that regulate cell growth and differentiation have important roles in normal cell physiology (30). If a proto-oncogene differentiates or starts to be expressed more than normal as a result of mutation or change in external stimulus; These changes cause uncontrolled growth and therefore malignant formations in the cell. With the mutation of proto-oncogenes, they turn into genes called oncogenes that stimulate continuous cell division [38, 39]. Protooncogenes can be grouped into 4 groups according to the biochemical properties of protein products [40, 41].

a.**Growth Factors:** Growth factors are signal molecules in polypeptide structure that are secreted out of the cell and stimulate differentiation in the target cell. They recognize the target cell with special receptors on the cell surface and stimulate differentiation in the cell. The best-known growth factor is the platelet-derived growth factor (PDGF)(9). Growth factors are proteins that weigh between 4000 and 60,000 daltons and can affect cellular activities even in small amounts. 6 Growth factors are substances that enable growth and proliferation in various cell types. Many growth factors such as epidermal growth factor (EGF), mesodermal growth factor (MGF), platelet-derived growth factor (PDGF), granulocyte colony-stimulating factor (G-KUF), granulocyte macrophage colony-stimulating factor (GM-KUF) are isolated 7. As a result of studies with antioxidants, it has been explained that antioxidants may have a common function with growth factors and also have effects on factors [42, 43].

b.**Epidermal Growth Factor (Epidermal growth factor, EGF):** It is a 53 amino acid polypeptide that is identical to Urogastron. It is found in many tissues and is released during platelet degranulation. Most cells have receptors for EGF. The most numerous receptors are found on epithelial cells; however, there are also receptors on endothelial cells, fibroblasts, and smooth muscle cells. It has chemotactic properties for epithelial cells, endothelium, and fibroblasts. It has the feature of stimulating angiogenesis and collagenase activity [44, 45].

FGF has also been studied in various animal models; After topical application to the wound in the guinea pig ear, basic FGF has been shown to accelerate epithelialization. Cell number and collagen content increased with subcutaneous injection in guinea pigs. Topical basic FGF has a positive effect on wound healing problems that can be caused by infection and diabetes in mice [46–49].


shown that the programmed cell death mechanism is lost in cancer cells. This mechanism is specifically controlled by the bcl 2 proto-oncogene. As a result of chromosomal translocations of this gene, it can be activated especially in lymphomas [57–59].

	- 1.**Mutations:** Changes occur in the structure of proteins encoded by oncogenes activated as a result of mutations such as point mutations and frameshifts. As a result of these, changes occur in the critical binding sites of the protein, and they lose their protein binding properties and cause cancer development by failing to fulfill their duties.
	- 2.**Gene Amplification:** Gene amplification occurs when the number of copies of a gene in the cell genome increases. The increase in gene copy number occurs especially with karyotype duplications. These formations are only seen quite frequently in tumor tissues.
	- 3.**Chromosomal Rearrangements:** Chromosomal rearrangements are mostly changes that occur in hematological malignant tumors. Chromosomal translocations, and inversions are the most common rearrangements [60–64]. The best example of chromosomal rearrangements of human proto-oncogenes is the (9;22) translocation. In approximately 95% of patients with chronic myeloid leukemia (CML), a reciprocal translocation occurs in bone marrow cells between chromosomes 9 and 22. As a result of this translocation, the Philadelphia chromosome, which is smaller than the normal 22 chromosome number, is formed [65–67]. As a result of this translocation, the abl protooncogene is transferred from its normal location 9q34.1 to chromosome 22. The abl gene joins in its new location ("Breakpoint cluster region") with a special sequence called bcr. The hybrid gene resulting from this fusion causes the synthesis of a new protein believed to be responsible for tumor formation in bone marrow cells. This new protein has tyrosine kinase activity and activates cell division to form tumors [8, 66, 67].

## *2.1.3.2 Tumor suppressor genes*

Tumor suppressor genes were found for the first time as a result of studies on retinoblastoma, one of the very rare hereditary cancer types. Retinoblastoma is the most common type of cancer among childhood eye cancers and occurs bilaterally in 20–30% of cases [68, 69]. All bilateral cases and 15% of unilateral cases show autosomal dominant inheritance. The gene responsible for this disease is the Rb1 gene located proximal to the long arm of chromosome 13 [70, 71]. As a result of chromosomal changes or point mutations, the functional protein related to this gene is either absent or unable to function in cells in tumor tissue. In such cases, hereditary mutation; is found in only one of the gene pairs and is therefore in a heterozygous state. In order for a tumor to develop in a person carrying the mutant gene, a new mutation must also occur in the normal partner of the mutant gene in the retinal cell(9). As a result of a second mutation, a tumor occurs when the other intact allele is changed or lost. This situation is also called loss of heterozygosity [72, 73], (**Figure 2**).

In hereditary retinoblastoma cancers, the first mutation occurred in the person either as a result of germline mutations or inherited from one of the

parents. In people carrying this gene, retinoblastoma occurs at a very early age [74]. As a result of studies on the localization of many tumor types that show oss of heterozygosity for chromosome 13 and the localization of other tumor suppressor genes, more than 20 tumor suppressor gene regions were identified, the main ones being p53, retinoblastoma, BRCA 1, BRCA 2 (**Table 1**) [76–80].

#### *2.1.3.2.1 p53 gene*

The p53 gene is located in band 13 of the short arm of human chromosome 17. This gene, which is about 20 kb long; encodes a 2.8 kb mRNA and its product is a core phosphoprotein of 393 amino acids of 53 kD (10). Nucleotide and amino acid sequence analyzes have shown that; The p53 gene contains 5 conserved regions from neopus to human during evolution. This region includes exons 1, 4, 5, 7, and 8. These conserved regions are thought to be essential sites for the p53 wild-type protein. Specifically, the DNA binding region of the p53 gene contains 2 SV40 tumor antigen binding (T-ag), a nuclear localization signal, and multiple phosphorylation sites (**Figure 3**). The p53 protein controls gene expression positively or negatively by stopping the cell cycle in the G1 phase and binding to specific sequences and transcription factors. Normal p53 protein stops the cell cycle and leads the cell to programmed cell death in the absence of appropriate differentiation or proliferation factors [81–85].

#### *Cancer Genes and Breast Cancers DOI: http://dx.doi.org/10.5772/intechopen.104801*


#### **Table 1.**

*Some tumor suppressor genes and the types of cancer they cause [75].*

#### **Figure 3.**

*Schematic structure of the p53 gene; TAS: Transcription activation region, protein binding region (HSP), SV40 wide T-antigen region, adenovirus E1b and papillomavirus E6 binding region, cellular Mdm2 binding region, nuclear localization signal (NLS), oligomerization region (OLIGO) and phosphorylation region (cdc2 and CDK). The 5 conserved regions in evolution are indicated by the letters I, II, III, IV, and V, and the hot spot regions are indicated by the letters A, B, C, D.*

#### *2.1.3.2.2 BRCA1 gene*

The chromosomal location of the BRCA 1 gene (Breast cancer susceptibility gene) was first identified in 1990 and cloned in 1994 [86]. The BRCA1 gene has 24 exons (20) with approximately 100,000 base pairs, occupying 4 cM, located in the q12–21 region of chromosome 17; It is a gene that encodes a tumor suppressor protein. The 11th exon of the BRCA1 gene, which is very large, constitutes 61% of the entire gene. The BRCA1 gene encodes a tumor-suppressing protein with DNA binding properties that negatively affect cancer formation [87]. Recent studies have shown that the product of the BRCA1 gene; It has been shown to be a zing-finger protein with a zinc-binding site at the amino end [87–89].

#### *2.1.3.2.3 Mutation distribution*

Breast tumors occur with the loss of both the wild-type allele of the BRCA1 gene at 17q [90]. Since there are 500 different types and the BRCA 1 gene is a large gene, the frequency of mutation is quite high. Several clinically important mutations have been found in this gene. While approximately 90% of these mutations are frameshift or nonsense mutations, the rest are mutations that cause changes in the stop codon and cause the immature protein to be made at the translation stage [35, 91–94]. Studies have been ongoing since the gene was cloned to develop a test that could detect familial cancer risk by detecting BRCA 1 mutations. The second most common group of mutations in the BRCA1 gene are 185delAG and 5382insG mutations [95, 96]. These constitute 10% of all mutations in the BRCA1 gene. These two mutations are seen with a frequency of approximately 10% in Ashkenazi and non-Ashkenazi Jews. The carrier rate of these mutations in the same group is 1%. Mutations 185delAG and 5382insG have also been shown to be found in Moroccan and non-Jewish families. The high incidence of deletions in the AG sequence at position 185 of BRCA1 has caused this region to be called the 'Hotspot' region. In germ-line mutation studies in all women, the incidence of breast cancer before the age of 40 was found to be 20% in 185delAG carriers [95, 97–99]. While the 5832insC mutation is most common in Russians and Jews of European origin, it is very low in Israeli Jews [100, 101]. The most common mutation in the Russian population is 4153delA4 (**Figure 4**) [102].

#### *2.1.3.2.4 The function of BRCA1*

The BRCA 1 protein is a ring-finger protein of 1863′ amino acids (45, 46, 47). BRCA 1 is made in the differentiated epithelial cells of developing organs during embryonic development and puberty development. A significant increase in the mRNA level of BRCA 1 has been observed in breast epithelial cells during pregnancy in women without cancer. BRCA 1 expression in humans is stimulated by estrogen and decreases after birth (38,48). Suppression of BRCA 1 expression increases growth in both normal cells and malignant mammary epithelial cells [86, 90, 93]. Since the BRCA1 gene was isolated, its functions have been thought to play a role in

**Figure 4.** *Mutation distribution in the BRCA1 gene.*

transcription, control the cell cycle, and be associated with DNA repair mechanisms. It is a gene that participates in DNA repair mechanisms by interacting with basic transcriptional mechanisms (with RNA polymerase II, Transcription factors TFIIH, TFIIE, and RNA helicase A). BRCA1 and BRCA2 proteins together provide a repair of DNA double-strand breaks in mitotic cells [103, 104] BRCA1 protein interacts with the gamma-tubulin subunits of the centrosome during mitosis, stopping the cell cycle and providing damage control in DNA [105].

## *2.1.3.2.5 BRCA2 gene*

BRCA2 is another tumor suppressor gene that was mapped to the long arm of the 13th chromosome by Wooster et al. in 1994 (7). The 13q12-13 region containing BRCA2 is also a region close to the retinoblastoma gene (36, 39). The BRCA2 gene is a 70 kb gene with 27 exons, occupies 6 cM, and the product of the gene is a protein consisting of 3418 amino acids(36). The fact that exon 3 is similar to transcription factors indicates that it may have a function in this direction (33,). BRCA2 has a large 11th exon just like BRCA1(50). This exon makes up about 58% of the whole gene [86, 106–108]. While the risk of breast cancer and ovarian cancer is higher in patients with germline mutations in this gene, 30–40% loss of heterozygosity is observed in patients with sporadic breast and ovarian cancer [109, 110]. Interestingly, almost all BRCA2 mutations are familial [111]. This theorizes that BRCA mutations can theoretically be traced back to an initial sporadic case and may indicate the presence of a 'founder effect'. The majority of mutations in the BRCA 2 gene cause a frameshift condition. The most common frameshift mutation is the 999del5 mutation, which is also seen in Iceland. Other than that, the mutations seen in other populations are as follows. Ashkenazi Jewish-6174delT, Dutch-5579insA, Finns- 8555 T > G, 999del5, IVS23-2A > G, French Canadians 8765delAG, 3398delAAAAG, Hungarians-9326insA, Pakistanis-3337C > T, Slovenians-IVS16-2A > G [112]. People with certain mutations of the BRCA2 gene increase the risk of breast cancer by causing hereditary breast-ovarian cancer syndrome. As a result of research, hundreds of mutations in the BRCA2 gene, many of which cause an increased risk of cancer, have been identified. BRCA2 mutations are usually the addition or loss of a small number of DNA base pairs in the gene. As a result of these mutations, the protein product of the BRCA2 gene is abnormal and does not work properly. Research emerges as a result of the inability of the dysfunctional BRCA2 protein to repair the damages in the DNA that make up the genome. As a result, there is an increase in mutations due to this faulty synthesis after unrepaired DNA damages, and some of these mutations can lead to uncontrolled division of cells and the formation of a tumor [107, 113, 114].

## **3. Conclusion**

By revealing the environmental and genetic factors that are effective in the development of breast cancer, which is a very important social problem, studies to prevent breast cancer gain hope. The incidence of breast cancer differs from country to country in the world. While Hawaii, California, and Canada are in the first place with an incidence of 80–90 per hundred thousand per year, the same value is only between 12 and 15 per hundred thousand in Japan. Although the majority of breast cancers are sporadic cases, 5–10% of all cases are hereditary. BRCA1 and BRCA2 genes are known to be effective in the development of breast cancer. The BRCA1 gene is thought to be responsible for 4–5% of all breast cancers and 45% of hereditary breast cancers. The risk of developing breast cancer up to the age of 70

in BRCA1 gene carriers is 94%. The rate of breast cancer cases occurring before the age of 30 is 25%. The BRCA 1 gene is responsible for half of all familial breast cancer cases and 80–90% of multiple breast and ovarian cancer cases. This shows that due to the importance of BRCA1 and BRCA2 genes in the etiology of breast cancer, detecting both BRCA1 and BRCA2 genes, especially in familial breast cancer cases, is important for public health. As a result, routine applications with rapid, reliable, and inexpensive methods to detect BRCA1 and BRCA2 gene mutations are known to be involved in the etiology of breast cancer in patients and families with multiple breast cancer or ovarian cancer or diagnosed with breast cancer at an early age may need to be seen as potential chemotherapy targets.

## **Conflict of interest**

There is no conflict of interest.

## **Author details**

Metin Budak1 \* and Hatice Segmen<sup>2</sup>

1 Faculty of Medicine, Department of Biophysics, Trakya University, Edirne, Turkey

2 Department of Neurology, Kanuni Sultan Suleyman Training and Research Hospital, Saglik Bilimleri University, Turkey

\*Address all correspondence to: genomicdna2@yahoo.com; metinbudak@trakya.edu.tr

© 2022 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.

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## **Chapter 6**
