TGF-beta and estrogen signaling interactions in breast cancer

A ubiquitous and potent systemic modulator of epithelial cell growth is the cytokine growth factor TGF-beta. The major cellular receptor mediating its effects is the type II membrane-bound receptor (TbetaRII). Breast cancer cells are frequently insensitive to TGF-beta anti-proliferative effects; yet lack significant mutations in signaling components. In this study, reduced membrane-bound TbetaRII was observed in TGF-beta resistant cells while no significant change was observed in mRNA levels. Additionally, resistance correlated with estrogen receptor (ERalpha) content.; A central and re-occurring factor in breast cancer etiology is the sex steroid hormone 17beta-estradiol (E2). This hormone acts primarily through the nuclear receptor ERalpha to enhance cellular proliferation. Because TGF-beta responsiveness was found to correlate with ERalpha expression, effects of E2 on TbetaRII were investigated. Using an enhanced receptor binding strategy, E2 was found to result in reduced TbetaRII membrane bound levels. Additionally, a recently described transcriptional co-repressor of TGF-beta signaling, c-ski, was found to be induced by physiological concentrations of E2 in MCF-7 cells.; Studies on the effects of TGF-beta on E2 signaling resulted in attenuation of E2-driven growth by TGF-beta. This attenuation was associated with decreased ERalpha protein levels via a proteosome-mediated degradation pathway in the cell line BT474, which does not respond to TGF-beta binding or TGF-beta growth modulation. Additionally, TGF-beta was found to increase the pro-inflammatory enzyme complex cyclooxygenase 2 in normal stromal and epithelial cells as well as in the malignant cell line MDA-MB-231. The products of this enzyme have been implicated in increased local estrogen production and enhanced tumorigenesis.