Abstract 2615: 19-Nor-2α-(3-hydroxypropyl)-1α,25-dihydroxy vitaminD3 (MART-10) is a potent cell growth regulator and tumor metastasis inhibitor in MCF-7 cells: a new emerging strategy against ER+ breast cancer.

Abstract

Abstract Aims: For estrogen receptor positive (ER+) breast cancer patients, hormone antagonist therapy is currently a standard regimen with a successful rate of 50 % to prevent cancer recurrence post radical surgery and radiation therapy. Recently, the active form of vitamin D3, 1α,25-dihydroxyvitamin D3 [1α,25(OH)2D3], has received much attention due to its potent antitumor effects in pre-clinical studies, yet its clinical application has been hampered by its hypercalcemia side effect. In this study, we investigated the in vitro effects of a new class of less-calcemic vitamin D analog, 19-nor-2α-(3-hydroxypropyl)-1α,25-dihydroxyvitamin D3 (MART-10), on ER+MCF-7 cells. Materials and Methods: Cell number counting was used to evaluate the antiproliferative effect of 1α,25(OH)2D3 and MART-10 on MCF-7 and MDA-MB-231 cells. Flow cytometry, western blot, q-RT/PCR, and cellular invasion and migration assays were conducted to compare the effects of 1α,25(OH)2D3 and MART-10 on cell cycle progression, apoptosis induction, protein and mRNA expression, and cancer cell metastasis of MCF-7 cells, respectively. Results: We demonstrate that in MCF-7 cells: (1) MART-10 is 500- to 1000-fold more potent than 1α,25(OH)2D3 in inhibiting cell growth and arresting them at G0/G1 phase, mediated by a greater induction of p21 and p27 expression. (2) MART-10 is more active than 1α,25(OH)2D3 in causing cell apoptosis through higher BAX/Bcl expression ratio and the subsequent cytochrome C release from mitochondria to cytosol without involving caspases. (3) MART-10 is more active than 1α,25(OH)2D3 in preventing cell invasion and migration with a greater upregulation of E-cadherin expression. No effects on MMP-2 and -9 were observed. (4) MART-10 upregulated CYP24A1 expression to a greater extent and for a longer period of time than 1α,25(OH)2D3, suggesting it can exert a greater vitamin D receptor (VDR) transactivation and is more resistant to CYP24A1-mediated degradation. (5) VDR is highly expressed in MCF-7 cells, but not in MDA-MB-231 cells, that may explain the greater 1α,25(OH)2D3 and MART-10 effects observed in MCF-7 cells. (6) MART-10 is more potent than 1α,25(OH)2D3 in suppressing ER expression. Conclusion: Based on our results, MART-10 is a promising vitamin D analog for the potential treatment of ER+ breast cancer. Further in vivo animal study is warranted. Citation Format: Shin-Cheh Chen, Kun-Chun Chiang, Horng-Heng Juang, Ling-Ling Hsieh. 19-Nor-2α-(3-hydroxypropyl)-1α,25-dihydroxy vitaminD3 (MART-10) is a potent cell growth regulator and tumor metastasis inhibitor in MCF-7 cells: a new emerging strategy against ER+ breast cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2615. doi:10.1158/1538-7445.AM2013-2615