Anjali Verma1, D Joshua Cohen2, Nofrat Schwartz3, Chandana Muktipaty4, Jennifer E Koblinski5, Barbara D Boyan6, Zvi Schwartz7. 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.
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. Published by Elsevier B.V.
BACKGROUND: Epidemiological studies indicate high serum 25(OH)D3 is associated with increased survival in breast cancerpatients. 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. Published by Elsevier B.V.
Entities:
Keywords:
24R,25-dihydroxyvitamin D(3); Breast cancer; Estrogen receptor α; Estrogen-receptor positive breast cancer; Natural cancer therapies; Vitamin D(3)