Cross‐talk between the Growth Factor and Estrogen Signaling Pathways in Control of Breast Cancer

Abstract

The specific hypothesis underlying our proposed research is that positive crosstalk between the growth factor and estrogen signaling pathways is the basis of the growth advantage of Estrogen Receptor (ER)‐positive breast cancer cells, and is the driving mechanism for ligand‐independent ER activation and endocrine therapy escape. First, we have observed that in ER‐positive breast cancer cells the expression of the gene RPS6KB1, encoding S6K1, is regulated by estrogen/ER. While many studies have addressed the regulation of S6K1 kinase activity, very little is known regarding the transcriptional regulation of S6K1 expression. We determined that ER cooperates with other transcription factors, including GATA‐3 and ERRα in regulating expression of the S6K1 gene. Second, it has been shown that ER phosphorylated as a consequence of growth factor signaling is a strong marker of endocrine treatment response. Phosphorylation is important for ER transactivational activity, and ligand‐independent phosphorylation of this site may be involved in development of endocrine resistance in vivo. While several kinases have been implicated in phosphorylation of ER, the exact mechanism of these events is unclear. We characterize the contribution of mTORC1 to phosphorylation of ER, its effect on transcriptional activity of ER, and the role in endocrine resistance.