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Retinoid Antagonism of Estrogen-responsive Transforming Growth Factor and pS2 Gene Expression in Breast Carcinoma Cells¹

Department of Medicine, University of Maryland Cancer Center, and Veterans Administration Medical Center, Baltimore, Maryland 21218 [J. A. F., Z-M. S.], and Cell Biology Section, Laboratory of Pulmonary Pathobiology, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709 [C. N., A. M. J.]

Exposure of MCF-7 breast carcinoma cells to estradiol results in an increase in transforming growth factor (TGF-) synthesis and secretion. Since TGF- is a potent inducer of proliferation in MCF-7 cells, the increase in TGF- production by estradiol is thought to play an important role in the estrogen stimulation of growth of these cells. Retinoic acid inhibits the proliferation of MCF-7 cells and antagonizes the estrogen stimulation of growth. Addition of retinoic acid resulted in a greater than 70% inhibition of estradiol-induced TGF- synthesis and secretion in MCF-7 cells. The increase in TGF- mRNA expression by estradiol was also inhibited by exposure of the cells to retinoic acid. Pretreatment of the cells with retinoic acid for 24 or 72 h caused more than 50 and 90% inhibition, respectively, of the estradiol-enhanced expression of TGF- mRNA. Expression of pS2 mRNA in MCF-7 cells was stimulated approximately 8-fold by estradiol. Retinoic acid treatment suppressed by greater than 80% both the basal and estradiol-induced pS2 mRNA expression. Retinoic acid modulation of the estrogen receptor gene mRNA was not responsible for the retinoic acid inhibition of the stimulation of pS2 and TGF- gene expression by estradiol, since estrogen receptor gene expression was increased rather than decreased in the presence of retinoic acid. The nuclear retinoic acid receptors and mRNA were expressed in MCF-7 cells and its retinoic acid-resistant derivative RROI. Addition of estradiol to MCF-7 cells resulted in a decreased expression of retinoic acid receptor mRNA; this reduction is prevented by the presence of retinoic acid.

These results indicate that retinoic acid can inhibit estradiol-induced TGF- and pS2 mRNA expression in MCF-7 cells. The suppression of TGF- expression may represent one possible mechanism by which retinoic acid antagonizes the stimulation of MCF-7 proliferation by estradiol.

¹ This work was partly supported by the Veterans Administration.

² To whom requests for reprints should be addressed, at University of Maryland at Baltimore, Cancer Center, Room S9D05, 22 S. Greene Street, Baltimore, MD 21201.

Received 12/18/91. Accepted 5/ 7/92.

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