Volume 271, Number 50, Issue of December 13, 1996 pp. 32105-32111
©1996 by The American Society for Biochemistry and Molecular Biology, Inc.

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Retinoic Acid-induced Expression of Apolipoprotein D and Concomitant Growth Arrest in Human Breast Cancer Cells Are Mediated through a Retinoic Acid Receptor RAR-dependent Signaling Pathway

(Received for publication, November 27, 1995, and in revised form, August 28, 1996)

Yolanda S. López-Boado , Michael Klaus ^¶ , Marcia I. Dawson and Carlos López-Otín

From the Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Universidad de Oviedo, 33006-Oviedo, Spain, ^¶ Pharma Division, Preclinical Research, F. Hoffmann-La Roche, 4002 Basel, Switzerland, and  Life Sciences Division, SRI International, Menlo Park, California 94025

Apolipoprotein D (apoD) is a human plasma protein, belonging to the lipocalin superfamily, that is produced by a specific subtype of highly differentiated breast carcinomas and that is strongly up-regulated by retinoic acid (RA) in breast cancer cells. In this work, we have examined the molecular mechanisms mediating the induction of apoD gene expression by retinoids in T-47D human breast cancer cells. Northern blot analysis revealed that Ro40-6055, a synthetic retinoid that selectively binds and activates the retinoic acid receptor RAR, induced the accumulation of apoD mRNA in breast cancer cells in a time- and dose-dependent manner. The time course analysis demonstrated that apoD mRNA was induced 14-fold over control cells after 48 h of incubation with 10⁸ M Ro40-6055. As little as 10¹¹ M of this retinoid induced apoD mRNA 5-fold over the control, whereas incubation with 10⁷ M Ro40-6055 induced maximally 15-fold over control cells. RAR-selective antagonists counteracted the inductive effects of all-trans-RA, 9-cis-RA, and Ro40-6055 on the expression of apoD, when present at the same concentration as the retinoid agonists. By contrast, RAR-, RAR-, and RXR-selective retinoids did not affect apoD gene expression. The retinoid agonist Ro40-6055 had an antiproliferative effect on T-47D cells, with maximal growth inhibition of approximately 60% obtained after 7 days of incubation with 10⁷ M. This antiproliferative effect could be counteracted by a 100-fold excess of the antagonist Ro41-5253. Treatment of the cells with retinoids that do not bind the nuclear retinoic acid receptors did not affect apoD expression, despite the fact that they did have a strong antiproliferative effect on T-47D cells. On the basis of these results, a role for RAR on apoD gene expression induction by retinoids in breast cancer cells is proposed.

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