title: 1α,25-dihydroxyvitamin D3 inhibits cell growth and NFκB signaling in tamoxifen-resistant breast cancer cells.
abstract: Resistance to antiestrogens is a major clinical problem in current breast cancer treatment and development of new treatment strategies for these tumors is highly prioritized. In this study, we have investigated the effects of 1α,25-dihydroxyvitamin D3 on the proliferation of tamoxifen-resistant cells. Further, we have investigated on a molecular level the effects of vitamin D on NFkB signaling in tamoxifen-resistant breast cancer cells. Parental human breast cancer MCF-7 cells and four tamoxifen-resistant sublines have been used to investigate the effects of 1α,25-dihydroxyvitamin D3 on cell proliferation using a colorimetric method, gene expression using quantitative PCR, protein phosphorylation using Western blot analysis and cellular localization of proteins using immunofluorescence microscopy. We found that 1α,25-dihydroxyvitamin D3 is able to strongly decrease the growth of both tamoxifen-sensitive and -resistant breast cancer cells and that this antiproliferative effect of 1α,25-dihydroxyvitamin D3 might be mediated via inhibition of the NFκB pathway. We found that 1α,25-dihydroxyvitamin D3 stimulates the gene expression of IkB, an NFκB-inhibiting protein, and that cells pretreated with 1α,25-dihydroxyvitamin D3 have a decreased sensitivity to TNFα stimulation. Further, we show that 1α,25-dihydroxyvitamin D3 treatment strongly decreases the TNFα-induced translocation of p65 into the nucleus. This manuscript reports novel findings regarding the effects of 1α,25-dihydroxyvitamin D3 on NFκB signaling in tamoxifen-resistant breast cancer cells and suggests that vitamin D might be interesting for further evaluation as a new strategy to treat antiestrogen-resistant breast cancers.
authors.affiliation: Danish Cancer Society Research Center, Unit of Cell Death and Metabolism, Breast Cancer Group, Strandboulevarden 49, DK-2100 Copenhagen, Denmark; Swedish University of Agricultural Sciences, Department of Biomedicine and Veterinary Public Health, Box 7028, SE-750 07 Uppsala, Sweden. Electronic address: johan.lundqvist@slu.se.
authors.forename: Johan
authors.initials: J
authors.lastname: Lundqvist
authors.affiliation: Danish Cancer Society Research Center, Unit of Cell Death and Metabolism, Breast Cancer Group, Strandboulevarden 49, DK-2100 Copenhagen, Denmark.
authors.forename: Christina W
authors.initials: CW
authors.lastname: Yde
authors.affiliation: Danish Cancer Society Research Center, Unit of Cell Death and Metabolism, Breast Cancer Group, Strandboulevarden 49, DK-2100 Copenhagen, Denmark.
authors.forename: Anne E
authors.initials: AE
authors.lastname: Lykkesfeldt
mesh_terms: D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D002117:Calcitriol / Q000008:administration & dosage* / Q000737:chemistry; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects* / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D020672:I-kappa B Proteins / Q000096:biosynthesis; D061986:MCF-7 Cells; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D013629:Tamoxifen / Q000627:therapeutic use
chemical_list: C083487:I kappa B beta protein; D020672:I-kappa B Proteins; D016328:NF-kappa B; D013629:Tamoxifen; D002117:Calcitriol
keywords: 1α,25-Dihydroxyvitamin D(3); Breast cancer; Tamoxifen-resistance; Vitamin D