Carcinogenesis Advance Access originally published online on November 27, 2006
Carcinogenesis 2007 28(5):1000-1007; doi:10.1093/carcin/bgl230
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Overexpression of ER and VDR is not sufficient to make ER-negative MDA-MB231 breast cancer cells responsive to 1
-hydroxyvitamin D5
IIT Research Institute, Chicago, IL 60616, USA, 1 Department of Surgical Oncology, University of Illinois at Chicago, Chicago, IL 60612, USA
* To whom correspondence should be addressed. Tel: +1 312 567 4970; Fax: +1 312 567 4931; Email: rmehta{at}iitri.org
1
-hydroxyvitamin D5 [1(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 1(OH)D5 treatment. Our results demonstrate that ER expression in ER-negative breast cancer cells (S30) did not increase the sensitivity to 1(OH)D5, whereas in ER-positive BT474 cells, the significant antiproliferative effect of 1(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 1(OH)D5 in MDA-MB231 and S30 cells, although VDR direct target gene CYP24 was more responsive to 1(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.
Abbreviations: CoA, co-activator; CoR, co-repressor; ER, estrogen receptor; 1(OH)D5, 1-hydroxyvitamin D5; PgR, progesterone receptor; RT-PCR, reverse transcription-polymerase chain reaction; VDR, vitamin D receptor
Received June 12, 2006; revised November 13, 2006; accepted November 17, 2006.