An EGF receptor inhibitor induces RAR-beta expression in breast and ovarian cancer cells.
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.
Grunt
Thomas W
TW
Signaling Networks Program, Division of Oncology, Department of Medicine I, Medical University of Vienna, Vienna, Austria. thomas.grunt@meduniwien.ac.at
Puckmair
Klaudia
K
Tomek
Katharina
K
Kainz
Birgit
B
Gaiger
Alexander
A
D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004789:Enzyme Activation; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008745:Methylation / Q000187:drug effects; D010051:Ovarian Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D011401:Promoter Regions, Genetic / Q000235:genetics; D011799:Quinazolines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D018168:Receptors, Retinoic Acid / Q000235:genetics / Q000378:metabolism*
D066246:ErbB Receptors; D011799:Quinazolines; D012333:RNA, Messenger; D018719:Erb-b2 Receptor Tyrosine Kinases; D018168:Receptors, Retinoic Acid; C082925:retinoic acid receptor beta; C088860:4-((3-bromophenyl)amino)-6,7-dimethoxyquinazoline