Hereditary Breast Cancer Syndromes

BRCA1 and Cell Cycling
BRCA1 has been associated with the orderly and efficient progression of the cell through the cell cycle, as originally suggested by studies of breast cancer cell lines demonstrating that BRCA1 and cyclin A RNA levels increased in parallel in response to hormone treatment. BRCA1 also has been shown to be phosphorylated in a cell cycle–dependent manner. Thus, BRCA1 may play a role in G1/S-phase checkpoint control or may be up-regulated during the cell cycle in response to cellular messages.

BRCA1 and Response to DNA Damage
Finally, BRCA1 appears to play an important role in response to DNA damage. BRCA1 complexes with Rad51 and BRCA2, both of which have been associated with the cellular response to double-strand DNA breaks. Rad51 is the human homologue to an Escherichia coli recombination and repair protein, RecA. Additional work in this area suggests a role for BRCA1 not just in response to damaged DNA, but also in the control of normal recombination and thus in genome integrity.

In further evaluating the role of BRCA1 and Rad51 in response to DNA damage, foci containing both proteins were visualized in the cell nucleus and shown to disperse in response to the presence of hydroxyurea, ultraviolet radiation, mitomycin C, and gamma radiation-all agents that induce double-strand breaks in DNA. After dispersal, BRCA1, BARD1, and Rad51 all accumulated in structures known to play a role in repairing damaged DNA.

Further attempts to identify clinically relevant damaging agents and repair pathways involving BRCA1 showed that doxorubicin and ultraviolet radiation down-regulate BRCA1 expression in a mutant p53 ovarian cancer cell line, suggesting that BRCA1-associated DNA repair may be dependent on p53 function.

Resistance to cis-diamine dichloroplatinum (CDDP) also has been associated with induction of BRCA1 expression, and antisense BRCA1 expression has been associated with CDDP sensitivity. Finally, BRCA1 nullizygous mouse embryonic stem cells have been shown to be hypersensitive to ionizing radiation and hydrogen peroxide and are unable to perform preferential transcription–coupled repair of oxidative DNA damage.115 Taken together, these data suggest that BRCA1 and BRCA2 associate with Rad51 and play a role in response to DNA damage, and they suggest a role for BRCA1 as a key guardian against malignant transformation. Why breast and ovarian cancer are the primary manifestations of BRCA1 mutations, and not widespread malignancy, remains an intriguing mystery.

Initial progress toward the identification of a second breast cancer susceptibility gene came from a linkage analysis of 22 families with multiple cases of early-onset female breast cancer and at least one case of male breast cancer. Linkage between male breast cancer and polymorphic genetic markers on band 13q12-13 identified the BRCA2 locus. In 1995, the partial sequence of BRCA2117 and six germ-line mutations that truncated the putative BRCA2 protein were published, and shortly thereafter, the complete DNA coding sequence and exonic structure of BRCA2 was published by another collaborative group.

Frequency of BRCA2-Associated Breast Cancer
No studies have been performed on BRCA2 in the general population because of the difficulty in screening the entire coding sequence for mutations. However, one study of selected breast cancer patients identified BRCA2 mutations in only 2.7% of women with breast cancer younger than 32 years. This finding suggests that BRCA2 mutations may contribute to fewer cases of early-onset breast cancer than do BRCA1 mutations. This observation is supported by studies identifying BRCA2 mutations in 10% to 20% of families at high risk for breast and ovarian cancer.

In contrast to BRCA1 mutations, in association with which almost all breast cancer appears in women, BRCA2 mutations are associated with a 6% lifetime risk of male breast cancer. Although in absolute terms this represents significantly less cancer risk to men than to women, the relative risk represents a similar 100-fold increase over the general population risk.

The first study to examine this issue after BRCA2 was identified estimated that BRCA2 mutations account for 14% of all male breast cancer. However, these estimates were generated from a cohort heavily weighted toward male breast cancer cases with a significant family history of female breast cancer; thus, 15% was thought to be an overestimate of attributable risk of male breast cancer for an unselected population. The only population-based study of the frequency of BRCA2 mutations in men with breast cancer who were unselected for family history supports this hypothesis. This study demonstrated a 4% prevalence of BRCA2 mutations in men identified from a cancer registry. However, this was a small study, and 30% of the subjects reported a family history of female breast or ovarian cancer, potentially biasing the results of this study as well.

The lack of more conclusive data reflects the fact that familial male breast cancer is very difficult to study because of the rarity of breast cancer in men and the even smaller number of cases that occur in first-degree or second-degree male relatives. In the past 100 years, only 16 families with two or more cases of male breast cancer have been reported in the literature. Analysis of these families suggests that familial male breast cancer is likely to be as heterogeneous as familial female breast cancer. In addition, more than one-half of these families with male breast cancer include first-degree relatives with other types of cancers, such as oropharyngeal, ovarian, and female breast cancer. Nine of the families for which data were available reported cases of female breast cancer.

In these families, average age at diagnosis of breast cancer in female relatives was 46 years; this is considerably younger than the average age at diagnosis in the general population (57 years) and is consistent with the findings in studies of familial breast cancer in females. Thus, the data from families with combined male and female breast cancer argue strongly for the existence of at least one additional male breast cancer susceptibility gene. One potential candidate, a germ-line mutation in the androgen receptor gene, has been identified in two families to date, supporting the belief that this is a very rare cause of inherited male breast cancer. More work is needed to further clarify the role of BRCA2 and other genes in susceptibility to male breast cancer; this currently remains an area of intensive study.

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