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Estrogen Receptor Expression Activates the Transcriptional and Growth-inhibitory Response to Retinoids without Enhanced Retinoic Acid Receptor Expression¹

Lady Davis Institute for Medical Research, SMBD Jewish General Hospital, McGill University, Montréal, Québec H3T 1E2, Canada [A. R., K. D., W. H. M.]; Dipartimento di Istologia and Embriologia Medica, Università di Roma "La Sapienza," 14,00161 Rome, Italy [C. N.]; Ligand Pharmaceuticals, San Diego, California 92121 [W. W. L.]; and Université de Montréal, Montréal, Québec, H3C 3J7 Canada [S. M.]

Estrogen receptor (ER)-positive human breast cancer cells are hormonally regulated and are inhibited by retinoids, whereas most ER-negative breast cancer cells are not. Here, we compared retinoid-induced transcriptional activation and growth inhibition in the ER-negative breast cancer cell line MDA-MB-231, stably transfected to express wild-type ER (S30), with that of the ER-positive MCF-7 line and the ER-negative parental line. Retinoids inhibited growth of the ER-expressing S30 clone but not of the parental MDA-MB-231 cells. Unlike a previously reported MDA-MB-231 subclone that was transfected to express a mutated ER (G400V), S30 did not express increased levels of retinoid receptor RNA or protein, nor was there increased binding activity to retinoid-responsive DNA elements. However, stable expression of ER increased retinoid activation of transcription of a retinoic acid (RA) response elements from the low level in MDA-MB-231 to approach the level of MCF-7. The restored growth inhibition and transcriptional regulation by RA were unaffected by treatment with ER agonists or antagonists. Transient expression of ER but not of other nuclear receptors in MDA-MB-231 cells also activated retinoid-induced transcription, showing that this response is specific to ER. Furthermore, the effect of exogenously expressed ER on retinoid response was much greater than that obtained by overexpression of RA receptor and/or retinoid X receptor . Finally, a panel of ER mutants showed that enhancement of retinoid-induced transcriptional activity was dependent on the integrity of the DNA binding domain.

¹ This work was supported by the Cancer Research Society, McGill Center for Translational Research; by Fonds pour la Formation de Chercheurs et l'Aide à la Recherche; by the London Life Award in Medical Research; and, in part, by the Associazione Italiana per la Ricerca sul Cancro. W. H. M. is a Scholar of the Medical Research Council of Canada, S. M. is a recipient of a Chercheur Boursier award from the Fond de Recherche en Santé de Quebec, and K. D. is supported by a Fonds de la Recherche en Santé du Quebec/Fonds pour la Formation et l'Aide à la Recherche studentship.

² To whom requests for reprints should be addressed, at Lady Davis Institute for Medical Research, 3755 Chemin de la Cote-Ste-Catherine, Montréal, Québec H3T 1E2, Canada. Phone: (514) 340-8222 ext. 4365; Fax: (514) 340-7576; E-mail: WMiller@LDI.JGH.mcgill.ca.

Received 6/24/98. Accepted 9/17/98.

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