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 of regulatory sequences. RAR-beta2 represents the main mediator of the antiproliferative effect of retinoids. RAR-beta2 re-expression causes reversal of cell transformation, cell cycle arrest, and restoration of cellular retinoid sensitivity. RAR-beta2 is thus a tumor suppressor. Western blotting with phospho-EGFR antibodies, colorimetric in vitro cell proliferation assays and reverse transcription-polymerase chain reaction demonstrated that the EGFR inhibitor PD153035 not only blocked activation of EGFR by EGF and inhibited cell growth, but also stimulated RAR-beta expression in MDA-MB-468 human breast and OVCAR-3 human ovarian carcinoma cells. Upregulation of RAR-beta mRNA by PD153035 was confirmed by real-time reverse transcription-polymerase chain reaction demonstrating a 34- to 38-fold increase. 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 at the CpG islands of the RAR-beta2 gene promoter P2 as demonstrated by methylation-specific polymerase chain reaction suggesting that PD153035 increases RAR-beta gene transcription by reducing the degree of cytosine methylation in the P2 promoter. These novel data on the ErbB/retinoid receptor cross-talk may be useful for designing future anticancer combination regimens.

[Proc Amer Assoc Cancer Res, Volume 46, 2005]