Retinoid modulation of estradiol-stimulated growth and of protein synthesis and secretion in human breast carcinoma cells.

All-trans-retinoic acid (RA) has been demonstrated to inhibit the growth of numerous breast carcinoma cell lines. In this study we demonstrated that RA inhibits estradiol stimulation of proliferation of the estrogen-dependent breast carcinoma cell lines MCF-7 and ZR-75. RA inhibition of MCF-7 breast carcinoma cell proliferation is associated with the marked stimulation of the synthesis and secretion of a 75,000 molecular weight protein. Minor stimulation of the synthesis and secretion of other proteins was also noted, including 160,000, 95,000, 89,000, 82,000, 52,000 and 46,000 molecular weight proteins. Increased synthesis and secretion of the Mr 75,000 protein was noted with as little as 10 nM RA. Stimulation of the synthesis and secretion of this protein occurred within 24 h of adding the retinoid and at the time of RA inhibition of cellular proliferation. RA stimulated the production and secretion of this protein both in the absence and presence of estradiol. Stimulation of the secretion and synthesis was not noted in the presence of difluoromethyl-ornithine or tamoxifen, both of which significantly inhibited cellular proliferation. The estrogen-dependent breast carcinoma cell line ZR-75 when exposed to RA also expressed increased synthesis of the Mr 75,000 and 46,000 proteins but increased synthesis was not noted in the RA-resistant cell line MDA-MB-231. Stimulation of the synthesis and secretion of the Mr 75,000 and/or 46,000 proteins may be intimately involved in RA inhibition of cellular proliferation.