Breast cancer is a complex, multifactorial disease with both genetic and environmental components. Germline mutations in the breast cancer susceptibility gene BRCA1 account for the increased risk of early onset of familial breast cancer, whereas overexpression of the ErbB family of receptor tyrosine kinases has been linked to the development of non-familial or sporadic breast cancer. The breast cancer susceptibility gene (BRCA1) encodes a nuclear phosphoprotein that acts as a tumor suppressor, while activation of the ErbB receptors by heregulin (HRG) promotes cell growth in breast epithelial cells. The possibility that ErbB-2 receptor activation by heregulin can modulate BRCA1 function presents a new approach and a novel mechanism in understanding breast cancer biology. To assess if there may be a link between these two regulatory molecules, we aim to investigate the effect of activation of the ErbB receptor pathway by HRG on BRCA1 function. Our recent studies showed that HRG stimulation induced the phosphorylation of BRCA1, which was mediated by the phosphatidylinositol-3 kinase (PI-3K)/AKT pathway. In addition, HRG as well as constitutively active p110 and AKT blocked the BRCA1-induced activation of the cyclin dependent kinase inhibitor p21WAF1/CIP1 promoter and the growth suppressive function of BRCA1. These results suggest that inhibition of BRCA1 function by HRG could contribute to the dysregulated cell growth associated with sporadic breast cancer. These data lead us to hypothesize that: (1) BRCA1 might play a role not only in the onset of familial breast cancer but also in sporadic breast cancer; (2) Inhibition of normal BRCA1 function by HRG could contribute to the dysregulated cell growth associated with sporadic breast cancer; and (3) BRCA1 expression and phosphorylation might be regulated by the Forkhead transcription factor (FKHRL1) and the phosphatase and tensin homolog located on chromosome (PTEN) via the PI-3K/AKT pathway. Therefore, the goal of this study is to examine the regulation of BRCA1 function and signaling in breast cancer cells upon HRG stimulation. The experiments presented here are designed to elucidate the mechanisms by which HRG modulates the function of BRCA1 and its regulation by PTEN and FKHRL1. These studies should provide a novel approach with new insights into the biology of BRCA1 and HRG function in breast cancer, and will assist in efforts to understand the regulation and function of BRCA1 mediated by growth factors in breast cancer development. In addition, these studies will provide a scientific basis for the manipulation of BRCA 1 for the treatment of this disease.
