24R,25-Dihydroxyvitamin D3 regulates breast cancer cells in vitro and in vivo

Anjali Verma, D. Joshua Cohen, Nofrat Schwartz, Chandana Muktipaty, Jennifer E. Koblinski, Barbara D. Boyan, Zvi Schwartz

Research output: Contribution to journalArticle

3 Scopus citations

Abstract

Background: Epidemiological studies indicate high serum 25(OH)D3 is associated with increased survival in breast cancer patients. Pre-clinical studies attributed this to anti-tumorigenic properties of its metabolite 1α,25(OH)2D3. However, 1α,25(OH)2D3 is highly calcemic and thus has a narrow therapeutic window. Here we propose another metabolite, 24R,25(OH)2D3, as an alternative non-calcemic vitamin D3 supplement. Methods: NOD-SCID-IL2γR null female mice with MCF7 breast cancer xenografts in the mammary fat pad were treated with 24R,25(OH)2D3 and changes in tumor burden and metastases were assessed. ERα66+ MCF7 and T47D cells, and ERα66- HCC38 cells were treated with 24R,25(OH)2D3 in vitro to assess effects on proliferation and apoptosis. Effects on migration and metastatic markers were assessed in MCF7. Results: 24R,25(OH)2D3 reduced MCF7 tumor growth and metastasis in vivo. In vitro results indicate that this was not due to an anti-proliferative effect; 24R,25(OH)2D3 stimulated DNA synthesis in MCF7 and T47D. In contrast, markers of invasion and metastasis were decreased. 24R,25(OH)2D3 caused dose-dependent increases in apoptosis in MCF7 and T47D, but not HCC38 cells. Inhibitors to palmitoylation, caveolae integrity, phospholipase-D, and estrogen receptors (ER) demonstrate that 24R,25(OH)2D3 acts on MCF7 cells through caveolae-associated, phospholipase D-dependent mechanisms via cross-talk with ERs. Conclusion: These results indicate that 24R,25(OH)2D3 shows promise in treatment of breast cancer by stimulating tumor apoptosis and reducing metastasis. General significance: 24R,25(OH)2D3 regulates breast cancer cell survival through ER-associated mechanisms similar to 24R,25(OH)2D3 effects on chondrocytes. Thus, 24R,25(OH)2D3 may modulate cell survival in other estrogen-responsive cell types, and its therapeutic potential should be investigated in ER-associated pathologies.

Original languageEnglish (US)
Pages (from-to)1498-1512
Number of pages15
JournalBiochimica et Biophysica Acta - General Subjects
Volume1863
Issue number10
DOIs
StatePublished - Oct 2019

Keywords

  • 24R,25-dihydroxyvitamin D
  • Breast cancer
  • Estrogen receptor α
  • Estrogen-receptor positive breast cancer
  • Natural cancer therapies
  • Vitamin D

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry
  • Molecular Biology

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  • Cite this

    Verma, A., Cohen, D. J., Schwartz, N., Muktipaty, C., Koblinski, J. E., Boyan, B. D., & Schwartz, Z. (2019). 24R,25-Dihydroxyvitamin D3 regulates breast cancer cells in vitro and in vivo. Biochimica et Biophysica Acta - General Subjects, 1863(10), 1498-1512. https://doi.org/10.1016/j.bbagen.2019.05.013