. 2019 Oct;1863(10):1498-1512.

doi: 10.1016/j.bbagen.2019.05.013. Epub 2019 May 22.

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

Anjali Verma¹, D Joshua Cohen², Nofrat Schwartz³, Chandana Muktipaty⁴, Jennifer E Koblinski⁵, Barbara D Boyan⁶, Zvi Schwartz⁷

Affiliations

¹ Department of Biomedical Engineering, Virginia Commonwealth University, 601 W. Main Street, Richmond, VA 23284, USA. Electronic address: vermaa3@vcu.edu.
² Department of Biomedical Engineering, Virginia Commonwealth University, 601 W. Main Street, Richmond, VA 23284, USA. Electronic address: djcohen@vcu.edu.
³ Department of Otolaryngology, Meir Hospital, Tchernichovsky St 59, Kfar Saba 4428164, Israel; Sackler Faculty of Medicine, Tel Aviv University, P.O. Box 39040, Tel Aviv 6997801, Israel; Department of Otolaryngology/Head and Neck Surgery, University of North Caroline Chapel Hill, 170 Manning Drive, Chapel Hill, NC 27599, USA.
⁴ Department of Biomedical Engineering, Virginia Commonwealth University, 601 W. Main Street, Richmond, VA 23284, USA. Electronic address: cmuktipaty@vcu.edu.
⁵ Department of Pathology, Virginia Commonwealth University, 401 N 13th Street, Richmond, VA 23298, USA; Massey Cancer Center, 401 College Street, Virginia Commonwealth University, Richmond, VA 23298, USA. Electronic address: Jennifer.koblinski@vcuhealth.org.
⁶ Department of Biomedical Engineering, Virginia Commonwealth University, 601 W. Main Street, Richmond, VA 23284, USA; Massey Cancer Center, 401 College Street, Virginia Commonwealth University, Richmond, VA 23298, USA; Wallace H. Coulter Department of Biomedical Engineering, 313 Ferst Drive NW, Georgia Institute of Technology, Atlanta, VA, USA. Electronic address: bboyan@vcu.edu.
⁷ Department of Biomedical Engineering, Virginia Commonwealth University, 601 W. Main Street, Richmond, VA 23284, USA; Department of Periodontics, University of Texas Health Science Center at San Antonio, 8210 Floyd Curl Drive, San Antonio, TX 78229, USA. Electronic address: zschwartz@vcu.edu.

PMID: 31125679
DOI: 10.1016/j.bbagen.2019.05.013

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

Anjali Verma et al. Biochim Biophys Acta Gen Subj. 2019 Oct.

. 2019 Oct;1863(10):1498-1512.

doi: 10.1016/j.bbagen.2019.05.013. Epub 2019 May 22.

Authors

Anjali Verma¹, D Joshua Cohen², Nofrat Schwartz³, Chandana Muktipaty⁴, Jennifer E Koblinski⁵, Barbara D Boyan⁶, Zvi Schwartz⁷

Affiliations

¹ Department of Biomedical Engineering, Virginia Commonwealth University, 601 W. Main Street, Richmond, VA 23284, USA. Electronic address: vermaa3@vcu.edu.
² Department of Biomedical Engineering, Virginia Commonwealth University, 601 W. Main Street, Richmond, VA 23284, USA. Electronic address: djcohen@vcu.edu.
³ Department of Otolaryngology, Meir Hospital, Tchernichovsky St 59, Kfar Saba 4428164, Israel; Sackler Faculty of Medicine, Tel Aviv University, P.O. Box 39040, Tel Aviv 6997801, Israel; Department of Otolaryngology/Head and Neck Surgery, University of North Caroline Chapel Hill, 170 Manning Drive, Chapel Hill, NC 27599, USA.
⁴ Department of Biomedical Engineering, Virginia Commonwealth University, 601 W. Main Street, Richmond, VA 23284, USA. Electronic address: cmuktipaty@vcu.edu.
⁵ Department of Pathology, Virginia Commonwealth University, 401 N 13th Street, Richmond, VA 23298, USA; Massey Cancer Center, 401 College Street, Virginia Commonwealth University, Richmond, VA 23298, USA. Electronic address: Jennifer.koblinski@vcuhealth.org.
⁶ Department of Biomedical Engineering, Virginia Commonwealth University, 601 W. Main Street, Richmond, VA 23284, USA; Massey Cancer Center, 401 College Street, Virginia Commonwealth University, Richmond, VA 23298, USA; Wallace H. Coulter Department of Biomedical Engineering, 313 Ferst Drive NW, Georgia Institute of Technology, Atlanta, VA, USA. Electronic address: bboyan@vcu.edu.
⁷ Department of Biomedical Engineering, Virginia Commonwealth University, 601 W. Main Street, Richmond, VA 23284, USA; Department of Periodontics, University of Texas Health Science Center at San Antonio, 8210 Floyd Curl Drive, San Antonio, TX 78229, USA. Electronic address: zschwartz@vcu.edu.

PMID: 31125679
DOI: 10.1016/j.bbagen.2019.05.013

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).

Published by Elsevier B.V.

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

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

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