24R,25-Dihydroxyvitamin D 3 regulates breast cancer cells in vitro and in vivo

Biochim Biophys Acta Gen Subj. 2019 Oct;1863(10):1498-1512. doi: 10.1016/j.bbagen.2019.05.013. Epub 2019 May 22.

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)2D3in 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.

Keywords: 24R,25-dihydroxyvitamin D(3); Breast cancer; Estrogen receptor α; Estrogen-receptor positive breast cancer; Natural cancer therapies; Vitamin D(3).

MeSH terms

  • 24,25-Dihydroxyvitamin D 3 / metabolism*
  • Animals
  • Breast Neoplasms / metabolism*
  • Breast Neoplasms / pathology
  • Cell Proliferation / drug effects
  • Estradiol / administration & dosage
  • Estradiol / pharmacology
  • Female
  • Humans
  • MCF-7 Cells
  • Mice
  • Mice, Inbred NOD
  • Phospholipase D / metabolism
  • Receptors, Estrogen / metabolism
  • Signal Transduction

Substances

  • Receptors, Estrogen
  • 24,25-Dihydroxyvitamin D 3
  • Estradiol
  • Phospholipase D