Triple-negative breast cancer is one of the least responsive
breast cancer subtypes to available targeted
therapies due to the absence of hormonal receptors, aggressive phenotypes, and the high rate of relapse. Early
breast cancer prevention may therefore play an important role in delaying the progression of
triple-negative breast cancer. Cancer stem cells are a subset of
cancer cells that are thought to be responsible for
tumor progression, treatment resistance, and
metastasis. We have previously shown that
vitamin D compounds, including a Gemini
vitamin D analog
BXL0124, suppress progression of
ductal carcinoma in situ in vivo and inhibit
cancer stem-like cells in MCF10DCIS mammosphere cultures. In the present study, the effects of
vitamin D compounds in regulating
breast cancer stem-like cells and differentiation in
triple-negative breast cancer were assessed. Mammosphere cultures, which enriches for
breast cancer cells with stem-like properties, were used to assess the effects of 1α,25(
OH)2D3 and
BXL0124 on cancer stem cell markers in the
triple-negative breast cancer cell line, SUM159.
Vitamin D compounds significantly reduced the mammosphere forming efficiency in primary, secondary and tertiary passages of mammospheres compared to control groups. Key markers of
cancer stem-like phenotype and pluripotency were analyzed in mammospheres treated with 1α,25(
OH)2D3 and
BXL0124. As a result, OCT4, CD44 and LAMA5 levels were decreased. The
vitamin D compounds also down-regulated the Notch signaling molecules, Notch1, Notch2, Notch3, JAG1, JAG2, HES1 and NFκB, which are involved in
breast cancer stem cell maintenance. In addition, the
vitamin D compounds up-regulated myoepithelial differentiating markers,
cytokeratin 14 and smooth muscle actin, and down-regulated the
luminal marker,
cytokeratin 18.
Cytokeratin 5, a
biomarker associated with basal-like
breast cancer, was found to be significantly down-regulated by the
vitamin D compounds. These results suggest that
vitamin D compounds may serve as potential preventive agents to inhibit
triple negative breast cancer by regulating cancer stem cells and differentiation.