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Open Access Highly Accessed Research article

Calcitriol restores antiestrogen responsiveness in estrogen receptor negative breast cancer cells: A potential new therapeutic approach

Nancy Santos-Martínez12, Lorenza Díaz1, David Ordaz-Rosado1, Janice García-Quiroz12, David Barrera1, Euclides Avila1, Ali Halhali1, Heriberto Medina-Franco3, María J Ibarra-Sánchez4, José Esparza-López4, Javier Camacho2, Fernando Larrea1 and Rocío García-Becerra1*

Author Affiliations

1 Departments of Reproductive Biology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Vasco de Quiroga No. 15, Tlalpan 14000 México, México

2 Department of Pharmacology, Centro de Investigación y de Estudios Avanzados, I.P.N., Av. Instituto Politécnico Nacional 2508 Gustavo A. Madero, 07360 México, D.F, México

3 Department of Surgery, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Vasco de Quiroga No. 15, Tlalpan 14000 México, D.F, México

4 Biochemistry Unit. Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Vasco de Quiroga No. 15, Tlalpan 14000 México, D.F, México

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BMC Cancer 2014, 14:230  doi:10.1186/1471-2407-14-230

Published: 29 March 2014

Abstract

Background

Approximately 30% of breast tumors do not express the estrogen receptor (ER) α, which is necessary for endocrine therapy approaches. Studies are ongoing in order to restore ERα expression in ERα-negative breast cancer. The aim of the present study was to determine if calcitriol induces ERα expression in ER-negative breast cancer cells, thus restoring antiestrogen responses.

Methods

Cultured cells derived from ERα-negative breast tumors and an ERα-negative breast cancer cell line (SUM-229PE) were treated with calcitriol and ERα expression was assessed by real time PCR and western blots. The ERα functionality was evaluated by prolactin gene expression analysis. In addition, the effects of antiestrogens were assessed by growth assay using the XTT method. Gene expression of cyclin D1 (CCND1), and Ether-à-go-go 1 (EAG1) was also evaluated in cells treated with calcitriol alone or in combination with estradiol or ICI-182,780. Statistical analyses were determined by one-way ANOVA.

Results

Calcitriol was able to induce the expression of a functional ERα in ER-negative breast cancer cells. This effect was mediated through the vitamin D receptor (VDR), since it was abrogated by a VDR antagonist. Interestingly, the calcitriol-induced ERα restored the response to antiestrogens by inhibiting cell proliferation. In addition, calcitriol-treated cells in the presence of ICI-182,780 resulted in a significant reduction of two important cell proliferation regulators CCND1 and EAG1.

Conclusions

Calcitriol induced the expression of ERα and restored the response to antiestrogens in ERα-negative breast cancer cells. The combined treatment with calcitriol and antiestrogens could represent a new therapeutic strategy in ERα-negative breast cancer patients.

Keywords:
Estrogen receptor; Breast cancer; Hormonal therapy; Calcitriol; VDR