Progesterone Regulation of Insulin Receptor Substrates Mediates Focal Adhesion Formation in Breast Cancer Cells.

摘要

Both progesterone and the IGFs are critically involved in the development of the mammary gland and breast cancer. How they interact with each other to regulate breast cancer progression is not clear yet. In this study, we found that progesterone potentiates IGF-I action in breast cancer cells. Specifically, IRS-2 expression was markedly induced by progesterone, while IRS- i and lOF-IR levels were not changed. This progesterone effect on IRS-2 was mediated by PR-B and via a transcriptional mechanism. Furthermore, progesterone treatment enhanced activation of IGF-I-induced Erk and Akt signaling downstrearn of IRS -2. Iterestingly, progesterone enhanced IGF-induced cell mobility while it showed no or little effect on cell cycle progression. This progesterone increase of IGF-I-induced cell motility was mediated by IRS-2 increase as blockade of IRS-2 expression by IRS-2 si-RNA transfection impaired the progest AND one effect, which was probably not via Erk and Akt signaling. These data, together with previous findings that IRS-2 is activated by integrins, suggest that IRS-2 may be involved in progestin increase of IGF- induced cell motility. Our study may also provide a clue to the question of why progestins in hormone replacement therapy would enhance the risk of breast cancer in comparison to estrogen use.