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Regulation of the Human Retinoic Acid Receptor Gene in the Estrogen Receptor Negative Human Breast Carcinoma Cell Lines SKBR-3 and MDA-MB-435¹

Department of Medicine, Division of Oncology and Cancer Center [A. K. R., A-M. S., X-S. L., R. G. B., J. A. F.] and Department of Biochemistry [T. M. G.], University of Maryland School of Medicine and Veterans Affairs Medical Center [J. A. F.], Baltimore, Maryland 21201; and SRI International, Menlo Park, California 94025 [M. I. D.]

Estradiol-mediated enhancement of retinoic acid receptor (RAR) 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 RAR 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 RAR 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 RAR-selective synthetic retinoids, we demonstrate that the antiproliferative effects of RA in the SKBR-3 cell line are accomplished, in part, via activation of RAR. 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 RAR 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 RAR promoter that contains unique cis elements responsible for mediating an estradiol-independent 2.5-fold enhancement of RAR gene expression in SKBR-3 and MDA-MB-435 cells.

¹ 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.).

² To whom requests for reprints should be addressed, at University of Maryland Cancer Center, Bressler Research Building, Room 9-031, 655 West Baltimore Street, Baltimore, MD 21201.

Received 5/ 3/96. Accepted 9/16/96.

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