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Molecular Cancer Research
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Cell Fate Decisions

The Relative Expression of ERα Isoforms ERα66 and ERα36 Controls the Cellular Response to 24R,25-Dihydroxyvitamin D3 in Breast Cancer

Anjali Verma, D. Joshua Cohen, Thomas W. Jacobs, Barbara D. Boyan and Zvi Schwartz
Anjali Verma
1Department of Biomedical Engineering, Virginia Commonwealth University, Richmond, Virginia.
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D. Joshua Cohen
1Department of Biomedical Engineering, Virginia Commonwealth University, Richmond, Virginia.
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Thomas W. Jacobs
1Department of Biomedical Engineering, Virginia Commonwealth University, Richmond, Virginia.
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Barbara D. Boyan
1Department of Biomedical Engineering, Virginia Commonwealth University, Richmond, Virginia.
2Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, Georgia.
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  • For correspondence: bboyan@vcu.edu
Zvi Schwartz
1Department of Biomedical Engineering, Virginia Commonwealth University, Richmond, Virginia.
3Department of Periodontics, University of Texas Health Science Center at San Antonio, San Antonio, Texas.
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DOI: 10.1158/1541-7786.MCR-20-0169 Published January 2021
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Abstract

Vitamin D3 and its metabolites have antitumorigenic properties in vitro and in vivo; however, clinical trials and retrospective studies on the effectiveness of vitamin D3 oral supplementation against cancer have been inconclusive. One reason for this may be that clinical trials ignore the complex vitamin D metabolome and the many active vitamin D3 metabolites present in the body. Recent work by our lab showed that 24R,25(OH)2D3, a vitamin D3 metabolite that is active in chondrocyte proliferation and differentiation, has antitumorigenic properties in estrogen receptor alpha-66 (ERα66)–positive (ER+) breast cancer, but not in ERα66-negative (ER−) breast cancer. Here we show that 24R,25(OH)2D3 is protumorigenic in an in vivo mouse model (NOD.Cg-PrkdcscidIl2rgtm1Wjl/SzJ (NSG) mice) of ER− breast cancer, causing greater tumor growth than in mice treated with vehicle alone. In vitro results indicate that the effect of 24R,25(OH)2D3 is via a membrane-associated mechanism involving ERs and phospholipase D. 24R,25(OH)2D3 increased proliferation and reduced apoptosis in ERα66-negative HCC38 breast cancer cells, and stimulated expression of metastatic markers. Overexpressing ESRI, which encodes ERα66, ERα46, and ERα36, reduced the proapoptotic response of ERα66− cells to 24R,25(OH)2D3, possibly by upregulating ERα66. Silencing ESR1 in ERα66+ cells increased apoptosis. This suggests 24R,25(OH)2D3 is differentially tumorigenic in cancers with different ERα isoform profiles. Antiapoptotic actions of 24R,25(OH)2D3 require ERα36 and proapoptotic actions require ERα66.

Implications: These results suggest that 24R,25(OH)2D3, which is a major circulating metabolite of vitamin D, is functionally active in breast cancer and that the regulatory properties of 24R,25(OH)2D3 are dependent upon the relative expression of ERα66 and ERα36.

Footnotes

  • Note: Supplementary data for this article are available at Molecular Cancer Research Online (http://mcr.aacrjournals.org/).

  • Mol Cancer Res 2021;19:99–111

  • Received February 20, 2020.
  • Revision received August 4, 2020.
  • Accepted October 12, 2020.
  • Published first October 20, 2020.
  • ©2020 American Association for Cancer Research.
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Molecular Cancer Research: 19 (1)
January 2021
Volume 19, Issue 1
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The Relative Expression of ERα Isoforms ERα66 and ERα36 Controls the Cellular Response to 24R,25-Dihydroxyvitamin D3 in Breast Cancer
Anjali Verma, D. Joshua Cohen, Thomas W. Jacobs, Barbara D. Boyan and Zvi Schwartz
Mol Cancer Res January 1 2021 (19) (1) 99-111; DOI: 10.1158/1541-7786.MCR-20-0169

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The Relative Expression of ERα Isoforms ERα66 and ERα36 Controls the Cellular Response to 24R,25-Dihydroxyvitamin D3 in Breast Cancer
Anjali Verma, D. Joshua Cohen, Thomas W. Jacobs, Barbara D. Boyan and Zvi Schwartz
Mol Cancer Res January 1 2021 (19) (1) 99-111; DOI: 10.1158/1541-7786.MCR-20-0169
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