Objective: Cancer stem cells (CSCs) are responsible for the drug resistance of breast cancers. Vitamin D deficiency promotes tumor resistance. The present study examined the effect of vitamin D and vitamin D receptor (VDR) expression on the tamoxifen resistance of CSCs. Methods: MCF-7 cells were treated with 1,25(OH)2D3 and their levels of VDR expression, viability, and apoptosis were detected. CD133+ MCF-7 stem cells were identified and transfected with a VDR-overexpression plasmid. The tamoxifen concentration that reduced MCF-7 cell viability by 50% (IC50) was determined. The activation of Wnt/β-catenin signaling was also investigated. Results: Vitamin D reduced the viability of MCF-7 cells and promoted their apoptosis. Vitamin D enhanced VDR expression and induced DNA damage. When CD133+ stem cells were separated from MCF-7 cells, the IC50 of tamoxifen for stem cells was significantly higher than that of parental MCF-7 cells, suggesting a higher tamoxifen resistance in MCF-7 stem cells. Levels of VDR expression and Wnt/β-catenin signaling in CD133+ cells were markedly lower and higher than those in CD133− cells, respectively. Stem cells transfected with VDR overexpression plasmids showed decreased tamoxifen IC50 values, viability, spheroid formation, and expression of Wnt and β-catenin proteins when compared with control cells. Cell apoptosis was increased by transfection with a VDR overexpression plasmid. Finally, the inhibitory effects induced by VDR overexpression could be reversed by the VDR inhibitor, calcifediol. Conclusion: Stem cells contributed to the tamoxifen resistance of MCF-7 cells. Vitamin D-induced VDR expression increased the sensitivity of MCF-7 stem cells to tamoxifen by inhibiting Wnt/β-catenin signaling.

PurposeBreast cancer is the most common cancer among women with ~1.67 million cases diagnosed annually worldwide, and ~1 in 37 women succumbed to breast cancer. Over the past decades, new therapeutic strategy has substantially improved the curative effect for women with breast cancer. However, the currently available ER-targeted and HER-2-based therapies are not effective for triple-negative breast cancer patients, which account for ~15% of total breast cancer cases.Materials and methodsWe reported that 1,25-(OH)2D3, a biologically active form of vitamin D3, exhibited a strong anticancer effects on the proliferation, migration, invasion, cell cycle arrest, and apoptosis of both ER-positive (MCF-7) and ER-negative breast cancer cells (MDA-MB-453).ResultsThe anticancer effect of 1,25-(OH)2D3 was more potent compared to the classical chemotherapeutics tamoxifen in MDA-MB-453 cells. Furthermore, we also found that 1,25-(OH)2D3 decreased the expression of Ras and resulted in decrease of the phosphorylation of downstream proteins MEK and ERK1/2, indicating that 1,25-(OH)2D3 plays its anticancer roles through targeting the Ras/MEK/ERK signaling pathway. In addition, Ras overexpression abrogated 1,25-(OH)2D3-induced G0/G1 cell cycle arrest and apoptosis of breast cancer cells, as well as the suppression of proliferation, migration, and invasion. Our study suggested that 1,25-(OH)2D3 suppressed breast cancer tumorigenesis by targeting the Ras/MEK/ERK signaling pathway.Conclusion1,25-(OH)2D3 might serve as a promising supplement for breast cancer drug therapy, especially for the ER-negative breast cancer and drug-resistant breast cancer.