Is there a Cytoplasmic Function of the Unliganded Vitamin D Receptor (VDR) in Controlling Breast and Prostate Cancer Growth?

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Is there a Cytoplasmic Function of the Unliganded Vitamin D Receptor (VDR) in Controlling Breast and Prostate Cancer Growth?Breast and prostate cancer are the most prevalent malignancies in western countries.Although diagnostic and therapeutic strategies have improved over the last decades, 20-40% of the patients will eventually develop bone metastases. Albeit, there have been recent developments in antitumour-treatment for metastatic bone disease, further studies are needed as it profoundly impairs the patient's quality of life and the prognosis of this malignancy remains poor.So far, it has been demonstrated that Vitamin D deficiency enhances breast and prostate cancer growth. Though, the exact mechanism by which Vitamin D has an influence on primary cancers and bone metastases continues to be unknown. Vitamin D is known to act on diverse systems on both normal and malignant cells. Most of the known effects are mediated to Vitamin D binding on the Vitamin D receptor (VDR). As the VDR is not only expressed in vitamin-D-responsive organs but also in malignant tumours, it is likely that the role of the VDR may go beyond its classical and well-known function as a simple ligand-specific receptor molecule.Very little is known about the ligand-independent actions of the VDR and cancer. A recently published study indicates that there is a ligand-independent role of the VDR that is in stark contrast to its known ligand-dependent effects.However, the exact mechanisms by which Vitamin D and the VDR may gain control over the progression of primary cancers and their skeletal secondaries remain unclear.Therefore the aim of this proposal is to explore the mechanisms by which the VDR controls human breast and prostate cancer growth in vitro and in vivo. The hypothesis is that the VDR possesses a ligand-independent role on cancer cell behaviour that is generic across a range of breast and prostate cancer cell lines in vitro and in vivo. For that purpose, several experiments on four cell lines including VDR knockdown and orthotopic, intraosseous and systemic (intracardial) implantation will be conducted using a total number of 200 mice.This survey may provide an excellent opportunity for the development of novel therapeutic agents for future cancer therapy.