title: Involvement of 1,25D3-MARRS (membrane associated, rapid response steroid-binding), a novel vitamin D receptor, in growth inhibition of breast cancer cells.
abstract: In addition to classical roles in calcium homeostasis and bone development, 1,25 dihydroxyvitamin D3 [1,25(OH)2D3] inhibits the growth of several cancer types, including breast cancer. Although cellular effects of 1,25(OH)2D3 traditionally have been attributed to activation of a nuclear vitamin D receptor (VDR), a novel receptor for 1,25(OH)2D3 called 1,25D3-MARRS (membrane-associated, rapid response steroid-binding) protein was identified recently. The purpose of this study was to determine if the level of 1,25D3-MARRS expression modulates 1,25(OH)2D3 activity in breast cancer cells. Relative levels of 1,25D3-MARRS protein in MCF-7, MDA MB 231, and MCF-10A cells were estimated by real-time RT-PCR and Western blotting. To determine if 1,25D3-MARRS receptor was involved in the growth inhibitory effects of 1,25(OH)2D3 in MCF-7 cells, a ribozyme construct designed to knock down 1,25D(3)-MARRS mRNA was stably transfected into MCF-7 cells. MCF-7 clones in which 1,25D3-MARRS receptor expression was reduced showed increased sensitivity to 1,25(OH)2D3 ( IC(50) 56+/-24 nM) compared to controls (319+/-181 nM; P<0.05). Reduction in 1,25D3-MARRS receptor lengthened the doubling time in transfectants treated with 1,25(OH)2D3. Knockdown of 1,25D3-MARRS receptor also increased the sensitivity of MCF-7 cells to the vitamin D analogs KH1060 and MC903, but not to unrelated agents (all-trans retinoic acid, paclitaxel, serum/glucose starvation, or the isoflavone, pomiferin). These results suggest that 1,25D3-MARRS receptor expression interferes with the growth inhibitory activity of 1,25(OH)2D3 in breast cancer cells, possibly through the nuclear VDR. Further research should examine the potential for pharmacological or natural agents that modify 1,25D3-MARRS expression or activity as anticancer agents.
authors.affiliation: Department of Human Health and Nutritional Sciences, University of Guelph, Guelph, Ontario, Canada N1G2W1.
authors.forename: Cynthia L
authors.initials: CL
authors.lastname: Richard
authors.forename: Mary C
authors.initials: MC
authors.lastname: Farach-Carson
authors.forename: Ben
authors.initials: B
authors.lastname: Rohe
authors.forename: Ilka
authors.initials: I
authors.lastname: Nemere
authors.forename: Kelly A
authors.initials: KA
authors.lastname: Meckling
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism; D000972:Antineoplastic Agents, Phytogenic / Q000378:metabolism; D001578:Benzopyrans / Q000378:metabolism; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D007529:Isoflavones / Q000378:metabolism; D017239:Paclitaxel / Q000378:metabolism; D016337:RNA, Catalytic / Q000378:metabolism; D018167:Receptors, Calcitriol / Q000235:genetics / Q000378:metabolism; D014212:Tretinoin / Q000378:metabolism; D014807:Vitamin D / Q000031:analogs & derivatives / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D000972:Antineoplastic Agents, Phytogenic; D001578:Benzopyrans; D007529:Isoflavones; D016337:RNA, Catalytic; D018167:Receptors, Calcitriol; D014807:Vitamin D; D014212:Tretinoin; C474837:pomiferin; D017239:Paclitaxel