HES1-mediated inhibition of Notch1 signaling by a Gemini vitamin D analog leads to decreased CD44(+)/CD24(-/low) tumor-initiating subpopulation in basal-like breast cancer.

Abstract

Tumor-initiating cells (also known as cancer stem cells) are the subpopulation of cells shown to be responsible for tumor initiation, maintenance and recurrence. In breast cancer, CD44(+)/CD24(-/low) cells were identified as tumor-initiating cells. We previously reported that a Gemini vitamin D analog, 1,25-dihydroxy-20R-21(3-hydroxy-3-deuteromethyl-4,4,4-trideuterobutyl)-23-yne-26,27-hexafluoro-cholecalciferol (BXL0124), reduced CD44(+)/CD24(-/low) cells in MCF10DCIS basal-like breast cancer cells. Since Notch has been identified as one of the key signaling pathways involved in breast cancer stem cells, the effect of BXL0124 on the Notch signaling pathway was investigated in breast cancer. The CD44(+)/CD24(-/low) subpopulation of MCF10DCIS cells showed elevated Notch1 signaling and increased cell proliferation compared to the CD44(+)/CD24(high) subpopulation. Treatment with the Gemini vitamin D analog BXL0124 decreased the level of activated Notch1 receptor. In addition, mRNA and protein levels of the Notch ligands, Jagged-1, Jagged-2 and DLL1, were significantly reduced by treatment with BXL0124, which was followed by repression of c-Myc, a key downstream target of Notch signaling. Interestingly, HES1, a known downstream target of Notch signaling, was rapidly induced by treatment with BXL0124. The inhibitory effect of BXL0124 on Notch signaling was reversed by knockdown of HES1. Overexpression of HES1 inhibited Notch1 signaling and reduced the CD44(+)/CD24(-/low) subpopulation, confirming a role of HES1 in Notch1 signaling. In conclusion, the Gemini vitamin D analog, BXL0124, represses the tumor-initiating subpopulation by HES1-mediated inhibition of Notch1 signaling. The present study demonstrates BXL0124 as a potent inhibitor of Notch signaling to target tumor-initiating cells in basal-like breast cancer. This article is part of a Special Issue entitled "17th Vitamin D Workshop".

• Authors: Jae Young So, Joseph Wahler, Soumyasri Das Gupta, David M Salerno, Hubert Maehr, Milan Uskokovic, Nanjoo Suh
• Journal: The Journal of steroid biochemistry and molecular biology (J Steroid Biochem Mol Biol) Vol. 148 Pg. 111-21 (Apr 2015) ISSN: 1879-1220 [Electronic] England
• PMID: 25541438 (Publication Type: Journal Article)
• Copyright: Copyright © 2014 Elsevier Ltd. All rights reserved.

Chemical References

• 1,25-dihydroxy-21-(3-hydroxy-3-methyl-4,4,4-tributyl)-23-yne-26,27-hexafluorocholecalciferol
• Basic Helix-Loop-Helix Transcription Factors
• CD24 Antigen
• CD24 protein, human
• CD44 protein, human
• Homeodomain Proteins
• Hyaluronan Receptors
• NOTCH1 protein, human
• RNA, Messenger
• RNA, Small Interfering
• Receptor, Notch1
• Receptors, Calcitriol
• Transcription Factor HES-1
• HES1 protein, human
• Calcitriol

Topics

• Apoptosis (drug effects)
• Basic Helix-Loop-Helix Transcription Factors (antagonists & inhibitors, genetics, metabolism)
• Blotting, Western
• Breast Neoplasms (drug therapy, metabolism, pathology)
• CD24 Antigen (metabolism)
• Calcitriol (analogs & derivatives, pharmacology)
• Carcinoma, Basal Cell (drug therapy, metabolism, pathology)
• Cell Proliferation (drug effects)
• Female
• Flow Cytometry
• Homeodomain Proteins (antagonists & inhibitors, genetics, metabolism)
• Humans
• Hyaluronan Receptors (metabolism)
• Microscopy, Fluorescence
• Neoplastic Stem Cells (drug effects, metabolism, pathology)
• RNA, Messenger (genetics)
• RNA, Small Interfering (genetics)
• Real-Time Polymerase Chain Reaction
• Receptor, Notch1 (antagonists & inhibitors, genetics, metabolism)
• Receptors, Calcitriol (antagonists & inhibitors, genetics, metabolism)
• Reverse Transcriptase Polymerase Chain Reaction
• Transcription Factor HES-1
• Tumor Cells, Cultured