RETINOIC ACID NUCLEAR RECEPTOR-BETA INHIBITS BREAST-CARCINOMA ANCHORAGE-INDEPENDENT GROWTH

Retinoids modulate cellular proliferation and mediate gene function th rough a series of nuclear receptors. The retinoic acid nuclear recepto r beta (RAR beta) plays an important role in the differentiation of a number of cell types. We now demonstrate that RAR beta expression is c onfined to normal mammary tissue and is not expressed in either immort alized normal or malignant cell lines. Treatment of RAR beta-transfect ed MDA-MB-231 cells with 1 mu M all-trans-retinoic acid (RA) significa ntly inhibited monolayer growth of the cells which express recombinant RAR beta. RAR beta-expressing MDA-MB-231 cells formed significantly s maller and fewer colonies in soft agar than the mock-transfected cells . Addition of 1 mu M RA stimulated colony size and number in the RAR b eta-transfected MDA-MB-231 cells. In contrast to the RAR beta-expressi ng cells, colony formation by the RAR alpha-expressing cells was simil ar to the mock-transfected controls and the addition of 1 mu M RA to t he RAR alpha-transfected cells inhibited colony formation. While demon strating decreased colony formation in agar, RAR beta-expressing MDA-M B-231 cells failed to exhibit decreased growth in SCID mice. Our resul ts show that RAR beta functions as a negative regulator of growth in b reast epithelial cells. In addition, the growth of these cells is diff erentially regulated by RAR alpha and RAR beta which is most likely th e result of the modulation of different genes. (C) 1995 Wiley-Liss, In c.