Relationship of p215^BRCA1 to tyrosine kinase signaling pathways and the cell cycle in normal and transformed cells

Abstract

We have analysed the relationship of the products of two genes, neu and BRCA1, known to be important in human breast cancer. Highly specific antibodies that recognized both the rodent and human form of the BRCA1 gene product (M_r 215 kDa, p215^BRCA1) were developed to facilitate these efforts. p215^BRCA1 was identified as a tyrosine phosphorylated protein primarily localized in the nucleus of several breast cancer cell lines. In transformed murine and human cells, levels of p215^BRCA1 tyrosine phosphorylation were inversely correlated with the activity of the erbB family receptor-tyrosine-kinases and with the transformed growth features of these cells. Regulation of p215^BRCA1 tyrosine phosphorylation was also related to events in the cell cycle. Increased levels of p215^BRCA1 phosphotyrosine content were observed in NIH3T3 cells arrested at the G₂/M transition. These findings indicate that the products of BRCA1, neu, and erbB breast cancer genes participate in a common or shared signaling pathway important in cell growth and its regulation.