BRCA1 and BRCA2: from molecular genetics to clinical medicine.

Abstract

Inherited susceptibility to breast cancer has been an area of intense investigation for the past 10 years. Early work focused on identifying modes of transmission, which culminated in the identification of chromosome 17q12-21 as the first human genomic region that harbored an autosomal dominant susceptibility gene for breast cancer (BRCA1) in 1990. BRCA1 was subsequently identified and was followed shortly by the identification of BRCA2. Research in the past 3 years has elucidated much about the mutation spectrum and mutation frequency of these genes in specific populations and is beginning to identify potential functions. Whereas progress in this area has been rapid and much is now known about inherited susceptibility to breast cancer, much more needs to be done to make these discoveries useful in the diagnosis, treatment, and ultimately, the prevention of breast cancer.

Regulation of BRCA1 by protein degradation

“…BRCA1 is a tumor suppressor gene whose inactivation is associated with a high incidence of familial breast and ovarian cancer (see Blackwood and Weber, 1998), and loss of BRCA1 function also has been implicated in the development of prostate cancer (Bishop and Kiemeney, 1997). BRCA1 over-expression can inhibit cell proliferation by transactivating p21 WAF1/CIP1 in both a p53-dependent and a p53-independent manner (Thompson et al, 1995;Somasundaram et al, 1997;Ouchi et al, 1998;Zhang et al, 1998).…”

Glomeruloid microvascular proliferation is associated with p53 expression, germline BRCA1 mutations and an adverse outcome following breast cancer

“…In breast cancer, both higher vascular endothelial growth factor (VEGF) levels (Blackwood and Weber, 1998;Linderholm et al, 2000) and increased microvessel density (MVD) (Weidner et al, 1991(Weidner et al, , 1992de Jong et al, 2000) are associated with a poorer prognosis. Recent microarray studies have also identified an association between the expression of genes involved in angiogenesis, such as VEGF, and poor prognosis following breast cancer (van't Veer et al, 2002).…”

4‐HPR modulates gene expression in ovarian cells

“…Both BRCA1 and BRCA2 function as tumor suppressor genes in the breast and ovary. 34,35,61 IOSE cells used in the study are thought to carry a BRCA mutation and originated from a woman with a strong family history of ovarian cancer, 34,61 The ovarian cancer cells OVCA433 had altered expression of BRCA genes, moreover, the expression of BRCA2 transcript in-frame exon 12 deletion (BRCA2D12) mRNA was also reported in these cells by Ho and coworkers. 61 4-HPR could directly affect mutant BRCA gene to suppress the ovarian carcinogenesis, which is a very important finding in this study and has significant implications for BRCArelated cancer prevention and merits further study.…”

“…Ovarian surface epithelial (OSE) cells originated from ovarian epithelial carcinomas in which women with a strong family history of ovarian carcinomas or with a mutation in one of the two known cancer suppressor genes-BRCA1 and BRCA2. 34,35 Since OSE cells are thought to be the site of origin of epithelial ovarian cancer, these cells are important to study their molecular and cellular properties compared to ovarian cancer cells to enhance our understanding of malignancy in ovarian cancer.…”