Breast Cancer Cells Induction of Retinoid Responses in SK-BR-3 and T 47 D Human Is Sufficient for Full α Activation of Retinoic Acid Receptor Updated

Retinoid signaling via retinoic acid (RA) and retinoid X receptors (RARs and RXRs) regulates mammary epithelial cell growth and differentiation. Loss of RAR-b might represent an early event during breast carcinogenesis. Higher differentiated, estrogen-dependent, estrogen receptor (ER)-positive (ER) mammary carcinoma cells have been found to contain relatively high levels of RAR-a and to be responsive to retinoids, whereas most undifferentiated, estrogen-independent, ER-negative (ER ) cells are characterized by low RARa expression and by retinoid resistance. In contrast, RAR-g is detectable at equal levels in both ER and ER cells. In the present investigation, we directly examined the relative contribution of the distinct retinoid receptors to the retinoid response of breast cancer cells by comparing the effects of low concentrations of specific retinoids, which selectively activate individual receptor subtypes, on growth, cell cycle distribution, apoptosis, and on the autoregulation of RAR-a and RAR-g in ER SK-BR-3 and ER T47D breast cancer cells. In vitro growth activity was determined by using a colorimetric cell viability assay and analysis of cell cycle distribution, and apoptosis was performed by flow cytometry of propidium iodide-stained or fluorescent Annexin V-labeled cells, respectively, whereas expression of RARa and RAR-g was determined by Northern blotting. Both cell lines are retinoid sensitive and express high amounts of RARa, RAR-g, and RXR-a. RAR-a-selective compounds (AM80 and AM580) inhibit cell growth, induce G1 arrest, stimulate apoptosis, and up-regulate RARa and RAR-g mRNA as efficiently as RAR/RXR-pan-reactive (9-cisRA) and RAR-panreactive retinoids (all-transRA, TTNPB). Remarkably, an RAR-a antagonist (Ro 41-5253) not only blocks the RARa-selective agonists but also the pan-reactive compounds. In contrast, RARb-selective (CD417), RARg-selective (CD437/AHPN), and RXRa-selective (Ro 25-7386) retinoids exert no effects on the examined parameters. Thus, our results support the idea that RAR-a is the crucial receptor mediating the biological effects during retinoid signaling in both ER 2 SK-BR-3 and ER T47D human breast cancer cells.

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