Mutations in the BRCA-1 and BRCA-2 genes are associated with a subset of breast and ovarian cancers. These two genes have different functions within cells. Like the other tumor suppressors discussed so far, mutations can arise spontaneously or they may be inherited. Individuals who inherit a BRCA-1 or BRCA-2 mutation are known to be more susceptible to developing breast cancer. Individuals carrying a BRCA mutation have a lifetime risk (if they live to the age of 85) of 80% for developing breast cancer. The lifetime risks for developing ovarian cancer is 10-20% for BRCA-2 mutations and 40-60% for BRCA-1 mutations. The presence of these mutations may also increase the risk of prostate, pancreatic, colon, and other cancers.The total risk for any person depends on the individual genetic and environmental risk factors to which they are exposed. BRCA-1 and BRCA-2 mutations are thought to be associated with 5-10% of all breast cancers.

The BRCA Genes and Estrogen
Mutation of the BRCA genes has been associated with cancers of certain tissues, including the breast and ovaries. This suggests that estrogen may play a role in the development of cancer in these tissues. Estrogen fluctuations, such as those seen during puberty, menstruation, pregnancy, and menopause are associated with cancer development. Increases in estrogen, especially at puberty and during pregnancy, cause an increase in breast epithelial cell proliferation, which in turn places increased demands on the DNA repair capabilities of the cells. Reproduction (cell division) of cells with lowered DNA repair efficiency may lead to the formation of cancer. In the animation below, estrogen (shown in pink) stimulates cells to divide, producing a cancerous cell. ⁽¹⁾

If one BRCA gene is already mutated, a mutation that removes the only functioning copy will cause DNA repair defects. When both copies of the repair gene are non-functional, there is an increased likelihood of a cell acquiring mutations that lead to tumor development. In an individual who has inherited a defective copy of the BRCA gene, ALL of their cells carry the defect. A mutation of the second copy in any cell can trigger DNA repair difficulties. Two independent mutation events are required for cancer development in individuals who have not inherited a defective BRCA allele. Both of these sporadic mutations must occur in the same cell. The occurrence of two mutations in the same cell is rare; this explains why these cancers tend to appear later in life.⁽¹⁾

More information on this topic may be found in Chapters 3,4,7, and 9 of The Biology of Cancer by Robert A. Weinberg.

A Closer Look at BRCA's Affects on Survival

There have been several studies designed to determine the differences in survival between BRCA mutation carriers with cancer and those who developed cancer sporadically. The results are somehwhat contradictory, probably due to differing study designs and factors such as the degree of matching between controls (sporadic) and carriers. However, though the BRCA mutation carriers have a poorer prognosis based on the characteristics of their cancer, they seem to have an equal or higher survival rate when compared with sporadic cancer patients. This is thought to be due to the responsiveness of the tumors to chemotherapy. The increased susceptibility may be due, in part, to their high proliferation( )rates. The tumors are also more susceptible to cancer treatments such as gamma radiation, cisplatin, and mitomycin C because those treatments cause DNA damage that would normally be repaired by functioning BRCA gene products. If the BRCA genes are inactive the cell can not repair DNA damage as efficiently and cell death results. The non-cancerous cells in a BRCA mutation carrier retain one functional BRCA gene and can therefore repair their DNA.⁽²⁾

BRCA Function

A Closer Look at BRCA's Affects on Survival