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Growth Inhibition of Human Breast Cancer Cells by 1,25-Dihydroxyvitamin D₃ Is Accompanied by Induction of Apolipoprotein D Expression¹

Departmento de Bioquímica y Biología Molecular [Y. S. L-B., X. S. P., S. A., C. L-O.] and Morfología y Biología Celular [J. T.], Facultad de Medicina, Universidad de Oviedo. 33006-Oviedo, Spain, and Department of Biology, Leo Pharmaceutical Products, Ballerup, Denmark [L. B.]

We have analyzed the effect of 1,25-dihydroxyvitamin D₃ on the expression of the gene encoding apolipoprotein D (apoD), a protein component of the human plasma lipid transport system that is overproduced by a specific subset of breast carcinomas. Northern blot analysis revealed that 1,25-dihydroxyvitamin D₃ strongly up-regulated apoD mRNA levels in T-47D human breast cancer cells in a time- and dose-dependent manner. The potency of this vitamin as an inducer of apoD expression was stronger than the effect observed for such steroid hormones as androgens and progesterone, described previously as hormonal up-regulators of apoD expression in these cells. A time course study demonstrated that the induction of apoD mRNA reached a level of 5-fold over the untreated cells after 48 h of incubation in the presence of 10^-7 M 1,25-dihydroxyvitamin D₃. A dose-response analysis showed that a 10^-6 M concentration of this vitamin consistently induced a maximal accumulation of 7-fold over the control cells. Similar up-regulatory effects on the apoD gene expression were obtained by treatment of T-47D cells with 1,25-dihydroxyvitamin D₃ analogues, including MC 903, which is relatively devoid of hypercalcemic side effects in clinical applications. Western blot analysis revealed that the inductive effect of 1,25-dihydroxyvitamin D₃ was also reflected at the protein level as an increase of immunoreactive protein in the conditioned media of vitamin-treated cells. This increased expression of apoD was accompanied by an inhibition of cell growth and morphological changes in T-47D cells. By contrast, we did not detect and inductive effect of 1,25-dihydroxyvitamin D₃ on apoD gene expression in MDA-MB-231 cells, which are refractory to the growth-inhibitory effects of this compound. On the basis of these results, we propose 1,25-dihydroxyvitamin D₃ as an important regulator of the expression of the apoD gene in breast carcinomas. We also suggest that apoD may be of interest as a biochemical marker of the action of 1,25-dihydroxyvitamin D₃ derivatives in current studies using these compounds as inhibitors of breast cancer cell growth or as chemotherapeutic agents in the prevention of breast cancer.

¹ This work was supported by Grant SAF94-0892 from Comisión Interministerial de Ciencia y Tecnología and a grant from Glaxo-Wellcome, Spain. X. S. P. is a recipient of a fellowship from FICYT-Asturias (Spain).

² To whom requests for reprints should be addressed. Phone: 34 85 104201; Fax: 34 85 103564.

Received 5/21/97. Accepted 7/14/97.

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