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

Oncogene volume 22, pages 4745–4751 (2003)Cite this article

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

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Acknowledgements

We acknowledge Dr Y Fu, Dr T Shepherd and D Lagace for critical reading of this manuscript, Drs R Grimshaw and J Bentley (QEII Health Science Centre) for providing human ovarian tumor samples, Dr Edward Leof (Mayo Clinic Cancer Center) for the antiphospho Smad3 antibody and EJ Campbell for technical assistance. This work was supported by funds from The National Cancer Institute of Canada (Grant 13631), Nova Scotia Health Research Foundation, and CaRE Nova Scotia. LDD is supported by the Rossetti Studentship for Cancer Research and MWN is a CIHR scholar.

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  1. Department of Pharmacology, Dalhousie University, 5850 College Street, Halifax, B3H 1X5, Nova Scotia, Canada

    Lesley Deanne Dunfield & Mark William Nachtigal

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  1. Lesley Deanne Dunfield
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  2. Mark William Nachtigal
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Correspondence to Mark William Nachtigal.

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Dunfield, L., Nachtigal, M. Inhibition of the antiproliferative effect of TGFβ by EGF in primary human ovarian cancer cells. Oncogene 22, 4745–4751 (2003). https://doi.org/10.1038/sj.onc.1206617

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