BRCA1 and BRCA2 and the genetics of breast and ovarian cancer

Abstract

Germline mutations in the tumor suppressor genes BRCA1 and BRCA2 predispose individuals to breast and ovarian cancers. Progress in determining the function of BRCA1 and BRCA2 suggests that they are involved in two fundamental cellular processes: DNA damage repair and transcriptional regulation. We evaluate current knowledge of BRCA1 and BRCA2 functions to explain why mutations in BRCA1 and BRCA2 lead specifically to breast and ovarian cancer. The BRCA1 and BRCA2 genes contain unusually high densities of repetitive elements. These features of the BRCAs genomic regions contribute to chromosomal instability of these genes. We propose that somatic alterations of BRCA1 and BRCA2 are common and driven by rearrangements between repetitive elements. Inherited and somatic mutations occur in BRCA1 and BRCA2; virtually all somatic mutations are the result of large genomic rearrangements. What are the consequences of such large somatic mutations of BRCA1 and BRCA2 in women with or without inherited mutations? The breast and ovary are estrogen-responsive tissues. Beginning in puberty, the breast epithelium proliferates rapidly in response to fluctuating levels of estrogen. We present a genetic model outlining how BRCA-deficient cells may gain uncontrolled proliferation leading to tumor formation. Central to this model of BRCA-mediated tumorigenesis are estrogen-mediated proliferation of breast and ovarian epithelium and the distinctive genomic context of the BRCA genes.

BRCA1 and BRCA2 mutations in Scotland and Northern Ireland

“…The ratio of breast to ovarian cancers is 2.39 : 1 for BRCA1 families and 6.18 : 1 for BRCA2 families, a difference which is significant at the 0.01% level by w 2 analysis. This is consistent with data from the Breast Cancer Linkage Consortium (Ford et al, 1998) and other sources (Risch et al, 2001;Welcsh and King, 2001). …”

UbcH10 expression may be a useful tool in the prognosis of ovarian carcinomas

“…It has been already (Welcsh and King, 2001) determined that approximately 10% of ovarian cancers arises in women who have inherited mutations in cancersusceptibility genes such as BRCA1, BRCA2 and other DNA repair genes. Conversely, the vast majority of ovarian cancers are sporadic, presumably resulting from the accumulation of genetic damage over lifetime.…”

Glucose-regulated protein 78 as a novel effector of BRCA1 for inhibiting stress-induced apoptosis

“…As an alternative approach, we utilized a BRCA1-specific small-interfering RNA (siRNA) approach. This may mimic the underexpression of BRCA1 commonly observed in ovarian and breast cancers despite the underlying mechanisms (Welcsh and King, 2001). Western blot and real-time (RT)-PCR analysis confirmed inhibition of endogenous BRCA1 after transfection with the BRCA1-specific siRNA compared with the control nonspecific siRNA (Figure 1c).…”

“…Germline mutation of BRCA1 is responsible for 30-40% of familial breast cancer cases. Familial ovarian cancer comprises at least 10% of cases (Welcsh and King, 2001). In addition, BRCA1 expression is often decreased or absent in sporadic breast and ovarian cancers, suggesting that BRCA1 may also play a role in nonhereditary tumors (Wilson et al, 1999;Zheng et al, 2000).…”

“…In addition, BRCA1 expression is often decreased or absent in sporadic breast and ovarian cancers, suggesting that BRCA1 may also play a role in nonhereditary tumors (Wilson et al, 1999;Zheng et al, 2000). The biological function of the BRCA1 protein appears to be complex as this protein has been implicated in the regulation of a variety of cellular processes including maintenance of genome integrity, DNA damage repair, cell cycle control and apoptosis (Welcsh and King, 2001). However, its molecular function remains unclear.…”