An EGF receptor inhibitor induces RAR-beta expression in breast and ovarian cancer cells.

Biochem Biophys Res Commun

Signaling Networks Program, Division of Oncology, Department of Medicine I, Medical University of Vienna, Vienna, Austria.

Published: April 2005

Inhibition of the epidermal growth factor (EGF)-receptor (EGFR) has become a promising anticancer treatment strategy. In addition, application of retinoids yields encouraging results for cancer prevention and therapy. Many tumors express no or low amounts of retinoic acid receptor-beta2 (RAR-beta2) due to epigenetic silencing via DNA hypermethylation. RAR-beta2 is the main mediator of the antiproliferative effect of retinoids. RAR-beta2 re-expression causes reversal of transformation, cell cycle arrest, and restoration of retinoid sensitivity. RAR-beta2 is thus a tumor suppressor. Western blotting, colorimetric in vitro cell proliferation assays, and reverse transcription-polymerase chain reaction demonstrated that the EGFR inhibitor PD153035 not only blocked activation of EGFR and inhibited cell growth, but also stimulated RAR-beta expression in MDA-MB-468 breast and OVCAR-3 ovarian carcinoma cells. Upregulation of RAR-beta by PD153035 was confirmed by real-time reverse transcription-polymerase chain reaction. In contrast, expression of other retinoid receptors and of estrogen receptor-alpha was not affected. PD153035-mediated re-induction of RAR-beta was associated with demethylation of the RAR-beta2 gene promoter P2 as demonstrated by methylation-specific polymerase chain reaction. These novel results on the ErbB/retinoid receptor cross-talk may be useful for designing future anticancer combination regimens.

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http://dx.doi.org/10.1016/j.bbrc.2005.02.104DOI Listing

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