Altered expression of BRCA1, BRCA2, and a newly identified BRCA2 exon 12 deletion variant in malignant human ovarian, prostate, and breast cancer cell lines

Germline mutations of BRCA1 and BRCA2 predispose to hereditary breast, ovar ian, and possibly prostate cancer, yet structural mutations in these genes are infrequent in sporadic cancer cases. To better define the involvement o f these genes in sporadic cancers, we characterized expression levels of BR CA1 and BRCA2 transcripts in cancer cell lines derived from neoplasms of th e ovary, prostate, and breast and compared them with those expressed in pri mary cultures of normal epithelial cells established from these organs. We observed upregulation of BRCA1 and/or BRCA2 expression in six of seven ovar ian cancer cell lines (OVCA420, OVCA429, OVCA432, ALST, DOV13, and SKOV3) w hen compared with levels found in normal ovary surface epithelial cells. Fu rthermore, five cancerous or immortalized prostatic epithelial cell lines ( BPH-1, TSU-Prl, LNCaP, PC-3, and DU145) also expressed higher levels of BRC A1 and/or BRCA2 mRNA than did primary cultures of normal prostatic epitheli al cells. In contrast, only the estrogen receptor-positive MCF-7 cell line overexpressed these messages, whereas the estrogen receptor-negative breast cancer cell lines Hs578T, MDA-MB-231, and MDA-MB-468 showed no change in e xpression levels when compared with normal breast epithelial cells. In addi tion, expanding on our recent identification of a novel BRCA2 transcript va riant carrying an In-frame exon 12 deletion (BRCA2 Delta 12), we report inc reased expression of this variant in several ovarian, prostate, and mammary cancer cell lines (OVCA420, OVCA433, ALST, DOV13, SKOV3, TSU-Prl, DU145, a nd MDA-MB-468). Most notably, high levels of BRCA2 Delta 12 mRNA were detec ted in an estrogen receptor-positive breast cancer cell line, MCF-7, and in an androgen-independent prostate cancer cell line, DU-145. Interestingly, the wild-type BRCA2 transcript was barely detectable in DU145, which could be used as a model system for future investigations an BRCA2 Delta 12 funct ion. Taken together, our data suggest disruption of BRCA1 and/or BRCA2 gene expression in certain epithelial cancer cell lines of the ovary, prostate, and breast. Because wild-type BRCA1 and BRCA2 gene products increase durin g cell-cycle progression and are believed to exert growth-inhibitory action , enhanced expression of these genes in cancer cells may represent a negati ve feedback mechanism for curbing proliferation in fast-growing cells. At p resent, the functionality of BRCA2 Delta 12 remains elusive. (C) 2000 Wiley -Liss, Inc.