title: Calcitriol restores antiestrogen responsiveness in estrogen receptor negative breast cancer cells: a potential new therapeutic approach.
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.
authors.forename: Nancy
authors.initials: N
authors.lastname: Santos-Martínez
authors.forename: Lorenza
authors.initials: L
authors.lastname: Díaz
authors.forename: David
authors.initials: D
authors.lastname: Ordaz-Rosado
authors.forename: Janice
authors.initials: J
authors.lastname: García-Quiroz
authors.forename: David
authors.initials: D
authors.lastname: Barrera
authors.forename: Euclides
authors.initials: E
authors.lastname: Avila
authors.forename: Ali
authors.initials: A
authors.lastname: Halhali
authors.forename: Heriberto
authors.initials: H
authors.lastname: Medina-Franco
authors.forename: María J
authors.initials: MJ
authors.lastname: Ibarra-Sánchez
authors.forename: José
authors.initials: J
authors.lastname: Esparza-López
authors.forename: Javier
authors.initials: J
authors.lastname: Camacho
authors.forename: Fernando
authors.initials: F
authors.lastname: Larrea
authors.affiliation: Departments of Reproductive Biology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Vasco de Quiroga No, 15, Tlalpan 14000 México, México. rocio.garciab@quetzal.innsz.mx.
authors.forename: Rocío
authors.initials: R
authors.lastname: García-Becerra
mesh_terms: D001943:Breast Neoplasms / Q000188:drug therapy / Q000473:pathology*; D002117:Calcitriol / Q000031:analogs & derivatives / Q000494:pharmacology*; D045744:Cell Line, Tumor; D019938:Cyclin D1 / Q000378:metabolism; D004958:Estradiol / Q000031:analogs & derivatives / Q000494:pharmacology; D020847:Estrogen Receptor Modulators / Q000494:pharmacology*; D047628:Estrogen Receptor alpha / Q000235:genetics* / Q000378:metabolism*; D005260:Female; D000077267:Fulvestrant; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D018167:Receptors, Calcitriol / Q000378:metabolism
chemical_list: C530104:CCND1 protein, human; C506487:ESR1 protein, human; D020847:Estrogen Receptor Modulators; D047628:Estrogen Receptor alpha; D018167:Receptors, Calcitriol; C579457:VDR protein, human; D019938:Cyclin D1; C055085:calcipotriene; D000077267:Fulvestrant; D004958:Estradiol; D002117:Calcitriol