Inhibition of the antiproliferative effect of TGFβ by EGF in primary human ovarian cancer cells

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Abstract
The majority of ovarian cancers (OCs) arise from the ovarian surface epithelium (OSE). Proliferation of the OSE can be regulated by a number of autocrine and paracrine factors, including transforming growth factor beta (TGF). Defects in the TGF signaling pathway have been implicated in a number of cancers, including ovarian. We previously found that the TGF signaling pathway is intact and functional in primary human OC cells, and that these cells stop growing in response to TGF. Ovarian cancer cells in vivo are exposed to TGF, yet continue to proliferate, therefore, mechanisms must exist to inhibit TGF signaling contributing to uncontrolled cellular proliferation. Numerous signaling pathways converge with the TGF pathway to modulate its effects, including signaling induced by epidermal growth factor (EGF). We hypothesized that EGF can modulate TGF signaling and contribute to uncontrolled cellular proliferation of OC cells. Our results show that EGF abrogates the antiproliferative effect of TGF. EGF does not modulate TGF signaling by inhibiting receptor-activated Smad (R-Smad) phosphorylation or nuclear translocation. Rather, EGF decreases TGF-induced mRNA expression of the cell cycle regulator, p15INK4B, contributing to decreased sensitivity of OC cells to the antiproliferative effect of TGF.