DNA repair capacity is associated with breast cancer risk. In a recent study, researchers examined one of many DNA repair mechanisms from cells from women with breast cancer and from their birth sisters who did not have breast cancer. Deficient DNA repair capacity was found to be associated with a three times greater risk of developing breast cancer. More research is needed regarding other DNA repair pathways, the association with breast cancer risk, and associated strategies to improve screening and prevention efforts (Kennedy, 2005).

Inherited genetic mutations are associated with a predisposition to develop breast cancer.

• Autosomal dominant mutations are estimated to account for 5-10% of breast cancers and are usually diagnosed 5-15 years earlier (e.g., diagnosed in women in their 40's) than sporadic cases of breast cancer.
• The predisposition for breast cancer is inherited but not everyone will develop cancer due to differences in how the mutation is expressed in men and women and incomplete penetration of the genetic mutation.
• Autosomal dominant mutations are passed from generation to generation, with children having about a 50% chance of inheriting the predisposition from the affected parent. Both males and females can inherit and pass on the mutation.
• Mutations of the BRCA1 and BRCA2 genes are some of the more common examples of inherited predisposition for breast and ovarian cancer. The BRCA1 and 2 genes are classified as tumor suppressor genes and are involved in the DNA repair pathway (mutations are thought to allow other DNA damage to accumulate).
• The BRCA1 mutation is located on chromosome 17 and accounts for about 45% of breast cancer in families with multiple cases of breast cancer only.
• The BRCA2 mutation is located on chromosome 13 and accounts for about 35% of breast cancer in familial breast cancer.
• BRCA1 and 2 mutation carriers have higher rates of additional breast cancer in the same or opposite breast, based on several studies.
• BRCA1 and/or 2 mutations are more common in certain sub-populations, e.g., Ashkenazi Jews, general Jewish population, and populations in the Netherlands, Iceland and Sweden (NCI, 2005d).

For more information on BRCA1 and 2 mutations, see "Additional resources & References."

• Mutations in the TP53 gene (a tumor suppressor and involved in the DNA repair pathway) account for less than 1% of breast cancer cases and are associated with Li-Fraumeni syndrome (NCI, 2005d).
• Mutations in the CHEK2 gene (involved in the DNA repair pathway) account for 4-11% of familial cases of breast cancer (NCI, 2005d).
• PTEN is a protein that functions as a tumor suppressor gene and mutations are associated with breast cancer and Cowden's Syndrome (NCI, 2005d).
   

Acquired or sporadic DNA mutations are acquired during a woman's lifetime, and are also the subject of current research. They are thought to contribute to a smaller individual predisposition for developing breast cancer (e.g., genetic susceptibility).

• Acquired mutations may be caused by chest radiation and cancer-causing chemicals, but the causes of most acquired mutations are not known at this time.
• These mutations, in combination with certain lifestyle and environmental factors, are thought to contribute to cancer development (Chen, 2005, and ACS, 2004e).

Estrogen and progesterone exposure

• Normal breast cells and most breast cancer cells have receptors that attach to circulating estrogen and progesterone. Estrogen and progesterone bind to the receptors and may work with growth factors (e.g., oncogenes and mutated tumor suppressor genes) to cause cancer cell growth and proliferation.
• Breast cancers that are estrogen and progesterone receptor positive (i.e., ER+ and PR+) are more likely to respond to hormonal therapy (e.g., tamoxifen) and have a better prognosis than cancers that are hormone receptor negative. This survival advantage is greatest among women under age 50 (Conde et al, 2004; Gran et al, 2005; NCI, 2005d).
   

HER2/neu (human epidermal growth factor receptor 2)
HER2/neu is a protein that stimulates cellular growth and is amplified and/or overexpressed in about 20-25% of invasive breast cancers.

• These cancers tend to grow faster, spread more rapidly, recur more often, and have a poorer prognosis than other breast cancers.
• Trastuzumab (Herceptin®) is FDA approved to treat metastatic breast cancer that is HER2/neu positive, and can be used by itself or in combination with other chemotherapy (ACS, 2004e).

African American women have a lower incidence of breast cancer than White women, but they continue to have higher breast cancer mortality rates than White and other minority women. African American women are also more likely to present with breast cancer at a younger age than White women (Chlebowski et al, 2005).

• The disparity in mortality rates for African American women is increasingly thought to be associated with both access to care factors (i.e., access and use of screening and treatment), and biological factors.
• Analysis of data from the Women's Health Initiative study revealed that African American women had more high-grade and estrogen receptor negative tumors, at a rate five times higher than for White women. Both findings make these aggressive breast cancers more difficult to treat and are associated with poorer outcomes (Chlebowski et al, 2005).
• Mutations in the TP53 gene were more common in African American women than in White women with breast cancer, based on a recent population-based study. Mutations in the TP53 tumor suppressor gene are associated with cancers that grow faster, are more likely to spread, and have a poorer prognosis (Jones et al, 2004).
• African American women with family histories of breast or ovarian cancer are much less likely to get genetic counseling about testing for BRCA mutations than White women, even though their risk is similar and after controlling for perceived risk and socioeconomic factors (Armstrong et al, 2005).