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, IC50 concentrations 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.