ESTROGEN UP-REGULATION OF BRCA1 EXPRESSION WITH NO EFFECT ON LOCALIZATION

Alterations in the expression of the breast and ovarian cancer suscept ibility gene BRCA1 may contribute to the development of mammary and ov arian neoplasia. The sex-steroid estrogen modulates cell proliferation of normal and neoplastic breast and ovarian epithelial cells, but the role of estrogen regulation on the expression of BRCA1 remains to be defined. In this study, estrogen-regulated BRCA1 expression was examin ed in breast and ovarian cancer cells. Estrogen stimulated the prolife ration of estrogen receptor (ER)-positive breast MCF-7, C7-MCF-7, and ovarian BG-1 cells as well as the expression of the estrogen-inducible pS2 gene. This was concomitant with upregulation of BRCA1 mRNA (2.5- to 5.0-fold) and a 3- to 10-fold induction of BRCA1 protein (230 kDa). Cell fractionation studies localized the BRCA1 protein to the nucleus in both unstimulated and estrogen-stimulated cells. The antiestrogen ICI-182780 inhibited estrogen-induced cell proliferation, BRCA1 mRNA i nduction, and BRCA1 protein expression in ER-positive cells. Conversel y, estrogen did not influence expression of BRCA1 in HBL-100 cells tha t lacked the estrogen receptor, although the constitutive levels of BR CA1 mRNA (but not protein) in these cells were 5- to 30-fold higher th an in other breast and ovarian cancer cells. Secretion of the BRCA1 pr otein into the cell medium did not account for the discrepancy between the mRNA and protein levels in HBL-100 cells. Proliferation of HBL-10 0 cells was not affected by either estrogen or ICI-182780. Taken toget her, these data support a role for the steroid estrogen and the involv ement of the estrogen receptor pathway in the modulation of expression of BRCA1.We therefore propose that stimulation of cell proliferation may be a prerequisite for upregulation of BRCA1 in breast and ovarian cancer cells. n/lol. Carcinog. 22:102-109, 1998. (C) 1998 Wiley-Liss, Inc.dagger