Anticancer activity of 1,25-[.sub.2][D.sub.3] against human breast cancer cell lines by targeting Ras/MEK/ERK pathway

Purpose: Breast 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 methods: We reported that 1,25-[(OH).sub.2][D.sub.3], a biologically active form of vitamin [D.sub.3], 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). Results: The anticancer effect of 1,25-[(OH).sub.2][D.sub.3] was more potent compared to the classical chemotherapeutics tamoxifen in MDA-MB-453 cells. Furthermore, we also found that 1,25-[(OH).sub.2][D.sub.3] decreased the expression of Ras and resulted in decrease of the phosphorylation of downstream proteins MEK and ERK1/2, indicating that 1,25-[(OH).sub.2][D.sub.3] plays its anticancer roles through targeting the Ras/MEK/ERK signaling pathway. In addition, Ras overexpression abrogated 1,25-[(OH).sub.2][D.sub.3]-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).sub.2][D.sub.3] suppressed breast cancer tumorigenesis by targeting the Ras/MEK/ERK signaling pathway. Conclusion: 1,25-[(OH).sub.2][D.sub.3] might serve as a promising supplement for breast cancer drug therapy, especially for the ER-negative breast cancer and drug-resistant breast cancer. Keywords: breast cancer, 1,25-[(OH).sub.2][D.sub.3], ER-negative, cell apoptosis, cell proliferation