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

• Published in: Biochemical and biophysical research communications 2005-04, Vol.329 (4), p.1253-1259
• Main Authors: Grunt, Thomas W., Puckmair, Klaudia, Tomek, Katharina, Kainz, Birgit, Gaiger, Alexander
• Format: Article
• Language: English
• Subjects: Breast Neoplasms - genetics; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Cell Line, Tumor; Cell Proliferation - drug effects; Cross-talk; EGFR inhibitor; Enzyme Activation; ErbB receptors; Female; Gene Expression Regulation - drug effects; Gene Expression Regulation, Neoplastic - drug effects; Humans; Methylation - drug effects; Ovarian Neoplasms - genetics; Ovarian Neoplasms - metabolism; Ovarian Neoplasms - pathology; Promoter Regions, Genetic - genetics; Quinazolines - pharmacology; RAR-β; Receptor, Epidermal Growth Factor - antagonists & inhibitors; Receptor, Epidermal Growth Factor - metabolism; Receptor, ErbB-2 - genetics; Receptor, ErbB-2 - metabolism; Receptors, Retinoic Acid - genetics; Receptors, Retinoic Acid - metabolism; Retinoid receptors; RNA, Messenger - genetics; RNA, Messenger - metabolism
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/j.bbrc.2005.02.104

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-β2 (RAR-β2) due to epigenetic silencing via DNA hypermethylation. RAR-β2 is the main mediator of the antiproliferative effect of retinoids. RAR-β2 re-expression causes reversal of transformation, cell cycle arrest, and restoration of retinoid sensitivity. RAR-β2 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-β expression in MDA-MB-468 breast and OVCAR-3 ovarian carcinoma cells. Upregulation of RAR-β by PD153035 was confirmed by real-time reverse transcription-polymerase chain reaction. In contrast, expression of other retinoid receptors and of estrogen receptor-α was not affected. PD153035-mediated re-induction of RAR-β was associated with demethylation of the RAR-β2 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.