CORRELATION OF RETINOID-BINDING AFFINITY TO RETINOIC ACID RECEPTOR-ALPHA WITH RETINOID INHIBITION OF GROWTH OF ESTROGEN RECEPTOR-POSITIVE MCF-7 MAMMARY-CARCINOMA CELLS

Both anchorage-dependent growth and anchorage-independent growth of th e estrogen receptor-positive mammary carcinoma cell line MCF-7 are inh ibited by all-trans-retinoic acid. This cell line has nuclear retinoic acid receptors (RARs) alpha and gamma. The natural retinoids all-tran s-retinoic acid and 9-cis-retinoic acid and a series of 12 conformatio nally restricted retinoids, which showed a range of binding selectivit ies for these receptors and had either agonist or antagonist activity for gene transcriptional activation by the RARs, were evaluated for th eir abilities to inhibit anchorage-dependent (adherent) and anchorage- independent (clonal) growth of MCF-7 cells. Correlation analyses were performed to relate growth inhibition by these retinoids with their bi nding affinity to RAR alpha or RAR gamma. Inhibition of anchorage-depe ndent growth in culture after 7 days of retinoid treatment correlated with binding to RAR alpha (n = 14; P less than or equal to 0.001) and not to RAR gamma (n = 14; P > 0.1). Both the RAR alpha-selective retin oid agonists and the two RAR antagonists that were evaluated inhibited adherent cell growth. The RAR gamma-selective agonists had very low g rowth inhibitory activity (< 10%) at concentrations as high as 125 mu M. These results suggest that RAR alpha is the retinoid recepter invol ved in the inhibition of adherent cell growth by retinoids and that tr anscriptional activation by this receptor on a RAR response element do es not appear to be required for this process to occur, For this serie s of retinoids, inhibition of anchorage-independent growth after 21 da ys of retinoid treatment only correlated (n = 12; P less than or equal to 0.005) with binding affinity to RAR alpha for the retinoid agonist s, although the RAR gamma-selective retinoids displayed weak activity. The RAR antagonists were very poor inhibitors of growth. These result s suggest that activation of gene transcription by RAR alpha appears t o be required for inhibition of anchorage-independent growth by retino ids in this estrogen receptor-positive mammary carcinoma cell line.