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National Institute of Environmental Health Sciences

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Your Environment. Your Health.

Publication Detail

Title: Analysis of the Transcriptome: Regulation of Cancer Stemness in Breast Ductal Carcinoma In Situ by Vitamin D Compounds.

Authors: Shan, Naing Lin; Minden, Audrey; Furmanski, Philip; Bak, Min Ji; Cai, Li; Wernyj, Roman; Sargsyan, Davit; Cheng, David; Wu, Renyi; Kuo, Hsiao-Chen D; Li, Shanyi N; Fang, Mingzhu; Maehr, Hubert; Kong, Ah-Ng; Suh, Nanjoo

Published In Cancer Prev Res (Phila), (2020 08)

Abstract: Ductal carcinoma in situ (DCIS), which accounts for one out of every five new breast cancer diagnoses, will progress to potentially lethal invasive ductal carcinoma (IDC) in about 50% of cases. Vitamin D compounds have been shown to inhibit progression to IDC in the MCF10DCIS model. This inhibition appears to involve a reduction in the cancer stem cell-like population in MCF10DCIS tumors. To identify genes that are involved in the vitamin D effects, a global transcriptomic analysis was undertaken of MCF10DCIS cells grown in mammosphere cultures, in which cancer stem-like cells grow preferentially and produce colonies by self-renewal and maturation, in the presence and absence of 1α25(OH)2D3 and a vitamin D analog, BXL0124. Using next-generation RNA-sequencing, we found that vitamin D compounds downregulated genes involved in maintenance of breast cancer stem-like cells (e.g., GDF15), epithelial-mesenchymal transition, invasion, and metastasis (e.g., LCN2 and S100A4), and chemoresistance (e.g., NGFR, PPP1R1B, and AGR2), while upregulating genes associated with a basal-like phenotype (e.g., KRT6A and KRT5) and negative regulators of breast tumorigenesis (e.g., EMP1). Gene methylation status was analyzed to determine whether the changes in expression induced by vitamin D compounds occurred via this mechanism. Ingenuity pathway analysis was performed to identify upstream regulators and downstream signaling pathway genes differentially regulated by vitamin D, including TP63 and vitamin D receptor -mediated canonical pathways in particular. This study provides a global profiling of changes in the gene signature of DCIS regulated by vitamin D compounds and possible targets for chemoprevention of DCIS progression to IDC in patients.

PubMed ID: 32467291 Exiting the NIEHS site

MeSH Terms: Breast Neoplasms/drug therapy*; Breast Neoplasms/genetics; Breast Neoplasms/pathology; Carcinoma, Ductal, Breast/genetics; Carcinoma, Ductal, Breast/pathology; Carcinoma, Ductal, Breast/prevention & control*; Carcinoma, Intraductal, Noninfiltrating/drug therapy*; Carcinoma, Intraductal, Noninfiltrating/genetics; Carcinoma, Intraductal, Noninfiltrating/pathology; Cell Line, Tumor; Cell Proliferation/drug effects; DNA Methylation/drug effects; Datasets as Topic; Disease Progression; Down-Regulation/drug effects; Epithelial-Mesenchymal Transition/drug effects; Epithelial-Mesenchymal Transition/genetics; Female; Gene Expression Regulation, Neoplastic/drug effects; Humans; Neoplasm Invasiveness/pathology; Neoplasm Invasiveness/prevention & control; Neoplastic Stem Cells/drug effects*; Neoplastic Stem Cells/pathology; RNA-Seq; Signal Transduction/drug effects; Signal Transduction/genetics; Up-Regulation/drug effects; Vitamin D/administration & dosage*; Vitamin D/analogs & derivatives

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