**1.1 Breast cancer and risk factors**

Breast cancer is the most common female cancer, the second most common cause of cancer death in women, and the main cause of death in women ages 40 to 59 (1). It has been reported that mortality rate from breast cancer has been significantly greater in women whose cancer was first diagnosed during pregnancy compared with those who had never been pregnant (2). Nowadays, many women all over the world faced the challenge of living with breast cancer. The lifetime probability of developing breast cancer is one in six overall (3). High prevalence of breast cancer and high mortality rate of women who stricken by, appoint it among the most challenging subjects in the area of experiments. The two major types of breast cancer risks are objective and subjective factors. Objective breast cancer risk is defined as an estimated chance for bearing breast cancer based on scientifically established risk factors for the disease and is predictive of resultant health outcomes. Subjective breast cancer risk is identified as an individual's realization of her chance for getting breast cancer based on her own cognitive appraisal and is affected by depressive conditions. Objective BC risk had a limited but significant relationship with immune response and natural killer cell activity (NKCA), whereas Subjective risk was highly associated with psychological distress but was not associated with NKCA also the results are still controversial (4).

Many factors including prenatal conditions, diet, physical activity, estrogen exposure, body mass index, depression and quality of life have been mentioned as breast cancer risk factors. A positive family history is the main risk factor. Diet with high amounts of alcohol, fat, caffeine and red meat is a positive risk factor for bearing breast cancer, whereas phytoestrogens and high amounts of calcium/vitamin D can be effective to reduce it (5,6).

Hormonal conditions stand among the most important factors. Prolonged exposure to and higher concentrations of endogenous estrogen; which is controlled and modulated by menarche, pregnancy, and menopause; increase the risk of breast cancer. Testosterone level has also showed some parallelism with higher rate of breast cancer in some studies, although not in all of them. Younger age of menarche and older age of first full-term pregnancy are associated with a higher risk of breast cancer. The data about the effects of oral contraceptives on breast cancer risk are controversial. Some studies show an increased risk of breast cancer in oral contraceptive users, whereas in some other researches, no significant difference was seen. The two newer researches didn't give any data which show

Breast Cancer from Molecular Point of View: Pathogenesis and Biomarkers 105

subtype. The basal-like subtype is named because it expresses many genes characteristic of

The name "luminal" derives from similarity in expression between these tumors and the luminal epithelium of the breast; they typically express luminal cytokeratins 8 and 18. These are the most common subtypes, make up the majority of ER-positive breast cancer, and are characterized by expression of ER, PR, and other genes associated with ER activation.

High expression of ER-related genes, low expression of the HER2 cluster of genes, and low expression of proliferation-related genes are the two main characters of Luminal A tumors. This kind has the best prognosis of all breast cancer subtypes. Whereas luminal B tumors have relatively lower (although still present) expression of ER-related genes, variable

Luminal B tumors carry a worse prognosis than luminal A tumors. Unfortunately, this

The HER2-enriched subtype (previously the HER2+/ER- subtype) is characterized by high expression of the HER2 and proliferation gene clusters, and low expression of the luminal cluster. For this reason, these tumors are typically negative for ER and PR, and positive for HER2. It is important to note that this subtype comprises only about half of clinically HER2 positive breast cancer. The rest have high expression of both the HER2 and luminal gene clusters and fall in a luminal subtype. Promotion in HER2-directed therapy has improved

The name of "basal-like" subtype comes from the similarity in gene expression to that of the basal epithelial cells. This subtype shows lower expression of the luminal and HER2 gene clusters. Therefore, these tumors are typically ER-, PR-, and HER2-negative on clinical assays. Because of this reason, the name "triple negative" is also used to describe them. However, while most triple negative tumors are basal-like, and most basal-like tumors are triple negative, there is significant inconsistency (up to 30 percent) between these two classifications. Although any subtype can be triple negative on clinical assays, an interesting subtype found in non-basal triple negative breast cancers is the more newly described claudin-low subtype, which is uncommon but interesting because of its expression of epithelial-mesenchymal transition genes and characteristics reminiscent of stem cells (9). Recently, many studies have focused on finding molecular pathways that play some roles in breast cancer pathogenesis. Mutation in oncogenes, pro-oncogenes and tumor suppressor genes has been remarked as potential elements in breast cancer. DNA amplication (mostly in proto -oncogenes, growth factors and their receptors) and DNA deletion (in tumorsuppressor genes) are repeatedly observed in breast tumors. Berouk him et al. found 76 amplications and 82 deletions in 243 breast tumors, in regions containing new possible sensitive genes, such as MCL1 and BCL2L1 (apoptosis), Interleukin-1 receptor-associated

expression of the HER2 cluster, and higher expression of the proliferation cluster.

normal breast basal epithelial cells.

**3.1 Luminal A and luminal B traits** 

subtype has high probability of recurrence.

**3.2 HER2-enriched subtype** 

the poor prognosis of this subtype.

**3.3 Basal-like subtype** 

**3. Luminal subtypes** 

that oral contraceptives cause any increase in breast cancer risk. Long term use of postmenopausal hormone therapy is associated with higher risk of breast cancer. In contrast, short-term HT appears not to increase the risk significantly, although it may make mammographic detection more difficult. Environmental toxic agents such as Organochlorines include polychlorinated biphenyls (PCB's), dioxins, and organochlorine pesticides such as DDT are weak estrogens with high lipophilic properties and as a result, can store in adipose tissues. Some studies suggest that exposure to these chemicals will increase the risk of bearing breast cancer, however the data are controversial and more researches should be done.

Age and gender are among the strongest risk factors for breast cancer. Breast cancer occurs 100 times more frequently in women than in men. Incidence rates increase with age until about the age of 45 to 50.

Ethnic difference is another factor affecting breast cancer prevalence. For example, in United States, breast cancer is more common among whites. Much of these differences arise from lifestyle factors and social conditions. Furthermore, there are marked variations in breast cancer incidence and mortality among countries Women with higher educational, occupational and economic level are at greater risk because of their reproductive pattern including age of parity and age of first birth. Ethnic differences in estrogen and progesterone receptor subtypes have been also determined as important factors that affect the probability of breast cancer (7). In a Multiethnic Cohort Study, various status of estrogen receptor (ER)/progesterone receptor (PR) including ER-/PR-, ER+/PR+, ER-/PR+ and ER+/PR- have been reported and ER/PR status varied significantly across racial/ethnic groups even within the same tumor stage. Compared to whites, the high prevalence of hormone receptor-negative tumors in African-American women may contribute to their high breast cancer mortality (8).
