Estradiol-mediated enhancement of retinoic acid receptor α (RARα) expression in the estrogen receptor (ER)-positive human breast carcinoma (HBC) cells results in their sensitivity to RA-mediated growth inhibition (A. K. Rishi et al., Cancer Res., 55: 4999–5006, 1995). Most ER-negative HBCs are known to express lower levels of RARα and are resistant to RA-mediated inhibition of growth. We show that ER-negative SKBR-3 and MDA-MB-435 HBCs express approximately 2-fold higher levels of RARα isoform 1 mRNA when compared to the ER-negative MDA-MB-231 and MDA-MB-468 HBCs. SKBR-3 cells are sensitive to growth inhibition by RA, and by using RARα-selective synthetic retinoids, we demonstrate that the antiproliferative effects of RA in the SKBR-3 cell line are accomplished, in part, via activation of RARα. Both MDA-MB-231 and MDA-MB-468 HBCs are not growth inhibited by RA or any of the retinoids tested. Transient transfection experiments using a 5.0-kb RARα promoter fragment fused to the luciferase reporter gene showed 2–3-fold higher transcriptional activation in SKBR-3 cells when compared to MDA-MB-468 cells. We report identification of a 72-bp fragment of RARα promoter that contains unique cis elements responsible for mediating an estradiol-independent 2.5-fold enhancement of RARα gene expression in SKBR-3 and MDA-MB-435 cells.
This work was supported in part by the medical research services of the Department of Veterans Affairs and by NIH Grant CA-63335 (J. A. F.).