TYROSINE KINASE SIGNALING PATHWAYS CONTROL THE EXPRESSION OF RETINOICACID RECEPTOR-ALPHA IN SK-BR-3 BREAST-CANCER CELLS

Breast carcinomas are frequently characterized by hyperactivated c-erb B receptor tyrosine kinase signaling. Combination of anti-proliferativ e retinoids with growth-inhibitory c-erbB-specific agents might induce therapeutic benefit. We demonstrate close interactions between the c- erbB and the retinoic acid receptor system in SK-BR-3 breast cancer ce lls, Epidermal growth factor and heregulin-beta 1 activate c-erbB rece ptors and dose- and time-dependently up-regulate retinoic acid recepto r-alpha (RAR-alpha) mRNA. Similar effects have been found for the grow th-inhibitory c-erbB-2 receptor tyrosine kinase-activating antibody 4D 5 and the tyrosine phosphatase inhibitor orthovanadate. In contrast, t he tyrosine kinase-inhibitor herbimycin A reduces tyrosine-specific pr otein phosphorylation and down-regulates RAR-alpha. Our data demonstra te that the expression of RAR-alpha, which represents a key mediator o f the anti-proliferative effects of retinoids in breast cancer cells, is regulated by modulators of tyrosine kinase signaling. The levels of RAR-beta and -gamma mRNAs, however, are not affected by such agents. (C) 1997 Elsevier Science Ireland Ltd.