Journal Article

Overexpression of ER and VDR is not sufficient to make ER-negative MDA-MB231 breast cancer cells responsive to 1α-hydroxyvitamin D<sub>5</sub>

Xinjian Peng, Pavan Jhaveri, Erum A. Hussain-Hakimjee and Rajendra G. Mehta

in Carcinogenesis

Volume 28, issue 5, pages 1000-1007
Published in print May 2007 | ISSN: 0143-3334
Published online November 2006 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/bgl230
Overexpression of ER and VDR is not sufficient to make ER-negative MDA-MB231 breast cancer cells responsive to 1α-hydroxyvitamin D5

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1α-hydroxyvitamin D5 [1α(OH)D5] is an active vitamin D analog showing promising chemopreventive effect in breast carcinogenesis. We previously reported that estrogen receptor (ER)-positive breast cancer cells were sensitive, whereas ER-negative breast cancer cells were relatively resistant to their antiproliferative effects. In the present study, we used ER-negative MDA-MB231, ER-transfected MDA-MB231 (S30) and ER-positive BT474 cell lines to evaluate the possible association between ER status and cellular sensitivity to 1α(OH)D5 treatment. Our results demonstrate that ER expression in ER-negative breast cancer cells (S30) did not increase the sensitivity to 1α(OH)D5, whereas in ER-positive BT474 cells, the significant antiproliferative effect of 1α(OH)D5 was correlated with the downregulation of ER and progesterone receptor expression. Further analysis indicated that both MDA-MB231 and S30 cells express low vitamin D receptor (VDR) at transcriptional level and protein level. However, transfection of VDR failed to restore the sensitivity to 1α(OH)D5 in MDA-MB231 and S30 cells, although VDR direct target gene CYP24 was more responsive to 1α(OH)D5 treatment in MDA-MB231 and S30 cells overexpressing VDR. In addition, nuclear receptor cofactors NCoR1 and SRC1 that could potentially affect VDR action were also low in both MDA-MB231 and S30 cells in comparison with ER-positive, vitamin D-sensitive BT474 cells. These results suggest that in addition to the increased ER and VDR expression, the intact VDR signaling machinery as present in ER-positive, vitamin D-sensitive cells is essential for the antiproliferative action of vitamin D, whereas the direct VDR target genes such as CYP24 can remain responsive to augmented VDR expression.

Journal Article.  6149 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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