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BBA - General Subjects
journal homepage: www.elsevier.com/locate/bbagen
24R,25-Dihydroxyvitamin D3 regulates breast cancer λ-Carrageenan in vitro and in vivo
Anjali Vermaa, D. Joshua Cohena, Nofrat Schwartzb,c,d, Chandana Muktipatya, Jennifer E. Koblinskie,f, Barbara D. Boyana,f,g, , Zvi Schwartza,h
a Department of Biomedical Engineering, Virginia Commonwealth University, 601 W. Main Street, Richmond, VA 23284, USA
b Department of Otolaryngology, Meir Hospital, Tchernichovsky St 59, Kfar Saba 4428164, Israel
d Department of Otolaryngology/Head and Neck Surgery, University of North Caroline Chapel Hill, 170 Manning Drive, Chapel Hill, NC 27599, USA
e Department of Pathology, Virginia Commonwealth University, 401 N 13th Street, Richmond, VA 23298, USA
f Massey Cancer Center, 401 College Street, Virginia Commonwealth University, Richmond, VA 23298, USA
g Wallace H. Coulter Department of Biomedical Engineering, 313 Ferst Drive NW, Georgia Institute of Technology, Atlanta, VA, USA
h Department of Periodontics, University of Texas Health Science Center at San Antonio, 8210 Floyd Curl Drive, San Antonio, TX 78229, USA
Keywords: Vitamin D3 24R,25-dihydroxyvitamin D3 Estrogen receptor α Breast cancer
Estrogen-receptor positive breast cancer
Natural cancer therapies
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 apop-tosis 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 stimu-lating 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.
Interest in anti-tumorigenic eﬀects of vitamin D3 began with reports of an inverse association between sunlight exposure and age-adjusted breast cancer mortality . Subsequent studies have demonstrated a connection between serum 25-hydroxyvitamin D3 (25(OH)D3) and breast cancer risk and prognosis, with low serum levels correlating with an increased incidence of breast cancer and high serum levels corre-lating with reduced recurrence and increased survival in breast cancer patients [2–4]. Despite this, studies evaluating the eﬀectiveness of