title: Vitamin D compounds inhibit cancer stem-like cells and induce differentiation in triple negative breast cancer.
abstract: 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)2D3and 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)2D3and 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.
authors.affiliation: Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, NJ, USA.
authors.forename: Naing Lin
authors.initials: NL
authors.lastname: Shan
authors.affiliation: Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, NJ, USA.
authors.forename: Joseph
authors.initials: J
authors.lastname: Wahler
authors.affiliation: Department of Food Science and Technology, Chung-Ang University, Anseong, South Korea.
authors.forename: Hong Jin
authors.initials: HJ
authors.lastname: Lee
authors.affiliation: Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, NJ, USA.
authors.forename: Min Ji
authors.initials: MJ
authors.lastname: Bak
authors.affiliation: Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, NJ, USA.
authors.forename: Soumyasri Das
authors.initials: SD
authors.lastname: Gupta
authors.affiliation: Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, NJ, USA.
authors.forename: Hubert
authors.initials: H
authors.lastname: Maehr
authors.affiliation: Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, NJ, USA; Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA. Electronic address: nsuh@pharmacy.rutgers.edu.
authors.forename: Nanjoo
authors.initials: N
authors.lastname: Suh
mesh_terms: D016588:Anticarcinogenic Agents / Q000737:chemistry / Q000494:pharmacology*; D002117:Calcitriol / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D006801:Humans; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000473:pathology; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D014815:Vitamins / Q000737:chemistry / Q000494:pharmacology*
chemical_list: C552206:1,25-dihydroxy-21-(3-hydroxy-3-methyl-4,4,4-tributyl)-23-yne-26,27-hexafluorocholecalciferol; D016588:Anticarcinogenic Agents; D014815:Vitamins; D002117:Calcitriol
keywords: Breast cancer; Mammosphere; OCT4; Stem cells; Vitamin D