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

非配体维生素D受体（VDR）在控制乳腺癌和前列腺癌生长中是否具有细胞质功能？乳腺癌和前列腺癌是西方国家最常见的恶性肿瘤，尽管在过去的几十年中诊断和治疗策略不断改进，但仍有20-40%的患者最终会发生骨转移。尽管近年来转移性骨疾病的抗肿瘤治疗取得了一些进展，但由于其严重损害患者的生活质量，且这种恶性肿瘤的预后仍然很差，因此还需要进一步的研究。迄今为止，已证实维生素D缺乏会促进乳腺癌和前列腺癌的生长。然而，维生素D对原发性癌症和骨转移的影响的确切机制仍然未知。已知维生素D作用于正常和恶性细胞的不同系统。大多数已知的作用是由维生素D与维生素D受体（VDR）结合介导的。由于VDR不仅在维生素D反应器官中表达，而且在恶性肿瘤中也表达，因此VDR的作用可能超出其作为简单配体特异性受体分子的经典和众所周知的功能。最近发表的一项研究表明，VDR具有配体非依赖性作用，这与其已知的配体依赖性作用形成鲜明对比。维生素D和维生素D受体控制原发性癌症和骨骼继发性癌症进展的确切机制尚不清楚，因此，本研究的目的是探索维生素D受体控制人类乳腺癌和前列腺癌生长的机制，体外和体内。该假设是VDR对癌细胞行为具有配体非依赖性作用，其在体外和体内的一系列乳腺癌和前列腺癌细胞系中是通用的。为此，将使用总共200只小鼠对四种细胞系进行几项实验，包括VDR敲除和原位、骨内和全身（心内）植入。

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.