Both anchorage-dependent growth and anchorage-independent growth of the estrogen receptor-positive mammary carcinoma cell line MCF-7 are inhibited by all-trans-retinoic acid. This cell line has nuclear retinoic acid receptors (RARs) α and γ. The natural retinoids all-trans-retinoic acid and 9-cis-retinoic acid and a series of 12 conformationally restricted retinoids, which showed a range of binding selectivities for these receptors and had either agonist or antagonist activity for gene transcriptional activation by the RARs, were evaluated for their 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 binding affinity to RARα or RARγ. Inhibition of anchorage-dependent growth in culture after 7 days of retinoid treatment correlated with binding to RARα (n = 14; P ≤ 0.001) and not to RARγ (n = 14; P > 0.1). Both the RARα-selective retinoid agonists and the two RAR antagonists that were evaluated inhibited adherent cell growth. The RARγ-selective agonists had very low growth inhibitory activity (< 10%) at concentrations as high as 12.5 µm. These results suggest that RARα is the retinoid recepter involved in the inhibition of adherent cell growth by retinoids and that transcriptional activation by this receptor on a RAR response element does not appear to be required for this process to occur. For this series of retinoids, inhibition of anchorage-independent growth after 21 days of retinoid treatment only correlated (n = 12; P ≤ 0.005) with binding affinity to RARα for the retinoid agonists, although the RARγ-selective retinoids displayed weak activity. The RAR antagonists were very poor inhibitors of growth. These results suggest that activation of gene transcription by RARα appears to be required for inhibition of anchorage-independent growth by retinoids in this estrogen receptor-positive mammary carcinoma cell line.
This research was supported by NIH Grants 1 P01 CA51993 (to M. I. D. and K. R. E.) and 1 R01 CA63335 (to J. A. F.).