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

1 Citation (Scopus)

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)
JournalBiochimica et Biophysica Acta - General Subjects
DOIs
StatePublished - Jan 1 2019

Fingerprint

Estrogen Receptors
Tumors
Phospholipase D
Cells
Apoptosis
Breast Neoplasms
Neoplasm Metastasis
Metabolites
Caveolae
MCF-7 Cells
Cell Survival
Cholecalciferol
Pathology
Lipoylation
Heterografts
Estrogens
Chondrocytes
Tumor Burden
Fats
Adipose Tissue

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

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. https://doi.org/10.1016/j.bbagen.2019.05.013

24R,25-Dihydroxyvitamin D3 regulates breast cancer cells in vitro and in vivo. / Verma, Anjali; Cohen, D. Joshua; Schwartz, Nofrat; Muktipaty, Chandana; Koblinski, Jennifer E.; Boyan, Barbara D.; Schwartz, Zvi.

In: Biochimica et Biophysica Acta - General Subjects, 01.01.2019.

Research output: Contribution to journalArticle

Verma, Anjali ; Cohen, D. Joshua ; Schwartz, Nofrat ; Muktipaty, Chandana ; Koblinski, Jennifer E. ; Boyan, Barbara D. ; Schwartz, Zvi. / 24R,25-Dihydroxyvitamin D3 regulates breast cancer cells in vitro and in vivo. In: Biochimica et Biophysica Acta - General Subjects. 2019.
@article{bfde224880ea4d59bb245f6a9b5bf0e7,
title = "24R,25-Dihydroxyvitamin D3 regulates breast cancer cells in vitro and in vivo",
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.",
keywords = "24R,25-dihydroxyvitamin D, Breast cancer, Estrogen receptor α, Estrogen-receptor positive breast cancer, Natural cancer therapies, Vitamin D",
author = "Anjali Verma and Cohen, {D. Joshua} and Nofrat Schwartz and Chandana Muktipaty and Koblinski, {Jennifer E.} and Boyan, {Barbara D.} and Zvi Schwartz",
year = "2019",
month = "1",
day = "1",
doi = "10.1016/j.bbagen.2019.05.013",
language = "English (US)",
journal = "Biochimica et Biophysica Acta - General Subjects",
issn = "0304-4165",
publisher = "Elsevier",

}

TY - JOUR

T1 - 24R,25-Dihydroxyvitamin D3 regulates breast cancer cells in vitro and in vivo

AU - Verma, Anjali

AU - Cohen, D. Joshua

AU - Schwartz, Nofrat

AU - Muktipaty, Chandana

AU - Koblinski, Jennifer E.

AU - Boyan, Barbara D.

AU - Schwartz, Zvi

PY - 2019/1/1

Y1 - 2019/1/1

N2 - 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.

AB - 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.

KW - 24R,25-dihydroxyvitamin D

KW - Breast cancer

KW - Estrogen receptor α

KW - Estrogen-receptor positive breast cancer

KW - Natural cancer therapies

KW - Vitamin D

UR - http://www.scopus.com/inward/record.url?scp=85066778574&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85066778574&partnerID=8YFLogxK

U2 - 10.1016/j.bbagen.2019.05.013

DO - 10.1016/j.bbagen.2019.05.013

M3 - Article

JO - Biochimica et Biophysica Acta - General Subjects

JF - Biochimica et Biophysica Acta - General Subjects

SN - 0304-4165

ER -