BRCA1 AS A POTENTIAL HUMAN PROSTATE TUMOR-SUPPRESSOR - MODULATION OF PROLIFERATION, DAMAGE RESPONSES AND EXPRESSION OF CELL REGULATORY PROTEINS

In addition to breast and ovarian cancer in women, recent evidence sug gests that germ-line mutations of the breast cancer susceptibility gen e-1 (BRCA1) also confer an increased life-time risk for prostate cance r in male probands, However, it is not known if and how BRCA1 function s in prostate cancer, We stably expressed wildtype (wt) and tumor-asso ciated mutant BRCA1 transgenes in DU-145, a human prostate cancer cell line with low endogenous expression of BRCA1, As compared with parent al cells and vector transfected clones, wtBRCA1 clones exhibited: (1) a slightly decreased proliferation rate (doubling time = 25 h as compa red with 22 h for control cells); (2) a (3-6)-fold increase in sensiti vity to chemotherapy drugs (adriamycin, camptothecin, and taxol); (3) increased susceptibility to drug-induced apoptosis; (4) reduced repair of single-strand DNA strand breaks; and (5) alterations in expression of key cellular regulatory proteins (including BRCA2, p300, Mdm-2, p2 1(WAF1/CIP1), Bcl-2 and Bar). Clones transfected with the 5677insA bre ast cancer-associated mutant BRCA1 (insBRCA1) displayed a similar phen otype to wtBRCA1 clones, except that insBRCA1 clones had a significant ly decreased proliferation rate (doubling time=42 h), On the other han d, cells transfected with with 185delAG mutant BRCA1 showed no obvious phenotype as compared with parental or vector transfected cells, Thes e findings suggest that BRCA1 may function as a human prostate tumor s uppressor by virtue of its ability to modulate proliferation and vario us components of the cellular damage response. They also suggest sever al potential target gene products for a BRCA1 prostate tumor suppresso r function.