Constitutive activation of JAK-STAT3 signaling by BRCA1 in human prostate cancer cells

Germ-line mutations of the breast cancer susceptibility gene 1 (BRCA1) conf er a high risk for breast and ovarian cancer in women and prostate cancer i n men. The BRCA1 protein contributes to cell proliferation, cell cycle regu lation, DNA repair and apoptosis; howe, er, the mechanisms underlying these functions of BRCA1 remain largely unknown, Here, we showed that, in Du-145 human prostate cancer cells, enhanced expression of BRCA1 resulted in cons titutive activation of signal transducer and activator transcription factor 3 (STAT3) tyrosine and serine phosphorylation, Moreover, Janus kinase 1 (J AK1) and JAK2, the upstream activators of STAT3, were also activated by BRC A1, Immunoprecipitation assay showed that BRCA1 interacted with JAK1 and JA K2, Blocking STAT3 activation using antisense oligonucleotides significantl y inhibited cell proliferation and triggered apoptosis in Du-145 cells with enhanced expression of BRCA1, These findings indicate that BRCA1 interacts with the components of the JAK-STAT signaling cascade and modulates its ac tivation, which may provide a new critical survival signal for the growth o f breast, ovarian and prostate cancers in the presence of normal BRCA1, (C) 2001 Federation of European Biochemical Societies. Published by Elsevier S cience B.V. All rights reserved.