The vitamin D receptor is involved in the regulation of human breast cancer cell growth via a ligand-independent function in cytoplasm
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Trupti Trivedi1,2, Yu Zheng1, Pierrick G.J. Fournier2,5, Sreemala Murthy2, Sutha John2, Suzanne Schillo1, Colin R. Dunstan3, Khalid S. Mohammad2, Hong Zhou1, Markus J. Seibel1,4, Theresa A. Guise2
1Bone Research Program, ANZAC Research Institute, University of Sydney, Sydney, Australia
2Division of Endocrinology, Department of Medicine, Indiana University-Purdue University at Indianapolis, Indianapolis, Indiana, USA
3Department of Biomedical Engineering, University of Sydney, Sydney, Australia
4Department of Endocrinology and Metabolism, Concord Hospital, Concord, Sydney, Australia
5Biomedical Innovation Department, Scientific Research and High Education Center from Ensenada (CICESE), Ensenada, Baja California, Mexico
Theresa A. Guise, email: email@example.com
Markus J. Seibel, email: firstname.lastname@example.org
Keywords: breast cancer, vitamin D, vitamin D receptor, ligand independent, bone metastasis
Received: November 04, 2016 Accepted: February 15, 2017 Published: March 01, 2017
Vitamin D has pleiotropic effects on multiple tissues, including malignant tumors. Vitamin D inhibits breast cancer growth through activation of the vitamin D receptor (VDR) and via classical nuclear signaling pathways. Here, we demonstrate that the VDR can also function in the absence of its ligand to control behaviour of human breast cancer cells both outside and within the bone microenvironment. Stable shRNA expression was used to knock down VDR expression in MCF-7 cells, generating two VDR knockdown clonal lines. In ligand-free culture, knockdown of VDR in MCF-7 cells significantly reduced proliferation and increased apoptosis, suggesting that the VDR plays a ligand-independent role in cancer cell growth. Implantation of these VDR knockdown cells into the mammary fat pad of nude mice resulted in reduced tumor growth in vivo compared with controls. In the intra-tibial xenograft model, VDR knockdown greatly reduced the ability of the cells to form tumors in the bone microenvironment. The in vitro growth of VDR knockdown cells was rescued by the expression of a mutant form of VDR which is unable to translocate to the nucleus and hence accumulates in the cytoplasm. Thus, our data indicate that in the absence of ligand, the VDR promotes breast cancer growth both in vitro and in vivo and that cytoplasmic accumulation of VDR is sufficient to produce this effect in vitro. This new mechanism of VDR action in breast cancer cells contrasts the known anti-proliferative nuclear actions of the VDR-vitamin D ligand complex.
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