Analysis of the transcriptome: regulation of cancer stemness in breast ductal carcinoma in situ by vitamin D compounds

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

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

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 1a25(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.

Original languageEnglish (US)
Pages (from-to)673-686
Number of pages14
JournalCancer Prevention Research
Volume13
Issue number8
DOIs
StatePublished - Aug 1 2020

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

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