Anticancer activity of 1,25-(OH)2D3 against human breast cancer cell lines by targeting Ras/MEK/ERK pathway.

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. We 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). The 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. 1,25-(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.