title: Vitamin D receptor as a target for breast cancer therapy.
abstract: Considerable epidemiological evidence suggests that high levels of circulating vitamin D (VD) are associated with a decreased incidence and increased survival from cancer, i.e., VD may possess anti-cancer properties. The aim of this investigation was therefore to investigate the anti-cancer potential of a low calcaemic vitamin D analogue, i.e., inecalcitol and compare it with the active form of vitamin D, i.e., calcitriol, in a panel of breast cancer cell lines (n= 15). Using the MTT assay, IC50concentrations for response to calcitriol varied from 0.12 µM to >20 µM, whereas those for inecalcitol were significantly lower, ranging from 2.5 nM to 63 nM (P= 0.001). Sensitivity to calcitriol and inecalcitol was higher in VD receptor (VDR)-positive compared to VDR-negative cell lines (P= 0.0007 and 0.0080, respectively) and in ER-positive compared to ER-negative cell lines (P= 0.043 and 0.005, respectively). Using RNA-seq analysis, substantial but not complete overlap was found between genes differentially regulated by calcitriol and inecalcitol. In particular, significantly enriched gene ontology terms such as cell surface signalling and cell communication were found after treatment with inecalcitol but not with calcitriol. In contrast, ossification and bone morphogenesis were found significantly enriched after treatment with calcitriol but not with inecalcitol. Our preclinical results suggest that calcitriol and inecalcitol can inhibit breast cancer cell line growth, especially in cells expressing ER and VDR. As inecalcitol is significantly more potent than calcitriol and has low calcaemic potential, it should be further investigated for the treatment of breast cancer.
authors.affiliation: UCD School of MedicineConway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin, Ireland alyson.murray@ucd.ie.
authors.forename: Alyson
authors.initials: A
authors.lastname: Murray
authors.affiliation: Division of Population Health SciencesRoyal College of Surgeons in Ireland, Dublin, Ireland.
authors.forename: Stephen F
authors.initials: SF
authors.lastname: Madden
authors.affiliation: UCD School of MedicineConway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin, Ireland.
authors.forename: Naoise C
authors.initials: NC
authors.lastname: Synnott
authors.affiliation: UCD School of Biomolecular and Biomedical ScienceUCD Conway Institute, University College Dublin, Dublin, Ireland.
authors.forename: Rut
authors.initials: R
authors.lastname: Klinger
authors.affiliation: Department of Molecular & Cellular TherapeuticsRoyal College of Surgeons Ireland, Dublin, Ireland.
authors.forename: Darran
authors.initials: D
authors.lastname: O'Connor
authors.affiliation: National Institute for Cellular Biotechnology (NICB)Dublin City University, Dublin, Ireland.
authors.forename: Norma
authors.initials: N
authors.lastname: O'Donovan
authors.affiliation: UCD School of Biomolecular and Biomedical ScienceUCD Conway Institute, University College Dublin, Dublin, Ireland.
authors.forename: William
authors.initials: W
authors.lastname: Gallagher
authors.affiliation: Department of Medical OncologySt. Vincent's University Hospital, Dublin, Ireland.
authors.forename: John
authors.initials: J
authors.lastname: Crown
authors.affiliation: UCD School of MedicineConway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin, Ireland.|UCD Clinical Research CentreSt. Vincent's University Hospital, Dublin, Ireland.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Duffy
mesh_terms: D000480:Alkynes / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000378:metabolism*; D002117:Calcitriol / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002762:Cholecalciferol / Q000494:pharmacology*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D018167:Receptors, Calcitriol / Q000235:genetics / Q000378:metabolism*; D011960:Receptors, Estrogen / Q000378:metabolism
chemical_list: D000480:Alkynes; D018167:Receptors, Calcitriol; D011960:Receptors, Estrogen; C579457:VDR protein, human; C409043:inecalcitol; D002762:Cholecalciferol; D002117:Calcitriol
keywords: breast cancer; calcitriol; inecalcitol; oestrogen receptors; vitamin D; vitamin D receptor