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Volume 271, Number 34, Issue of August 23, 1996 pp. 20346-20352
©1996 by The American Society for Biochemistry and Molecular Biology, Inc.

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The AF-2 Region of the Retinoic Acid Receptor  Mediates Retinoic Acid Inhibition of Estrogen Receptor Function in Breast Cancer Cells

(Received for publication, December 6, 1995, and in revised form, April 5, 1996)

M. A. Christine Pratt , Dave Deonarine , Christine Teixeira , Denise Novosad , Bonnie F. Tate and Joseph F. Grippo

From the  Department of Pharmacology, University of Ottawa, Ottawa, Ontario K1H 8M5, Canada and the  Department of Metabolic Diseases, Hoffmann-La Roche Inc, Nutley, New Jersey 07110

The growth of estrogen receptor (ER)-positive breast cancer cells is inhibited by all-trans-retinoic acid (RA). In the present study, estrogen (E2) induction of pS2 mRNA levels was significantly reduced within 6 h following cotreatment with RA. In transient transfection experiments, RA repressed transactivation from a vitellogenin E2-responsive element by approximately 50% and wild-type RA receptor  (RAR) or RAR enhanced this inhibition. Transfection of truncated RAR mutants terminating before or at amino acid 412 markedly decreased RA inhibition of E2-induced reporter gene activity. Expression of RARs with deletions of amino acids 413 and 414 in the transactivation-2 (AF-2) domain also reduced RA inhibition, while deletions and point mutations beyond amino acid 414 behaved like the wild-type RAR. RA-treated MCF-7 cells transfected with an RAR AF-2 region mutant were twice as sensitive to growth inhibition as untransfected and vector-transfected control cells. Thus, the AF-2 domain in the C terminus of the RAR mediates RA inhibition of ER-induced transcription in breast cancer cells. In addition, transcriptional interference between RARs and ERs may contribute to RA inhibition of ER-positive breast cancer cell growth.

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