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

• Applicant: Privatdozent Dr. Konstantin Alexander Horas
• Subject Area: Orthopaedics, Traumatology, Reconstructive Surgery ; Endocrinology, Diabetology, Metabolism
• Term: from 2013 to 2015
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 238133511

• Final Report Year: 2015

Final Report Abstract

Breast cancer is amongst the most prevalent malignancies globally with up to 40% of patients developing metastatic disease. The social and economic burden imposed by primary and metastatic breast cancers cannot be underestimated. A major outcome of this research project is a more detailed understanding of the role of the VDR in controlling tumour behaviour in breast cancer metastases to bone. In specific, it shows that loss of the VDR in breast cancer promotes cell invasiveness and enhances their metastatic potential to spread to bone. This is scientifically significant as it addressed fundamental mechanisms on how cancer cells become metastatic. This research may help to explain the inconsistencies in the associations between vitamin D and tumour outcomes found in clinical studies, as the effects of vitamin D on tumour behaviour are likely to depend on VDR status. A novel function of the VDR in common malignancies such as breast and prostate cancer has potential therapeutic significance. Thus, the mechanisms underlying the effects of the VDR on tumour cells, once fully revealed, may be exploited to control cancer growth and malignant potential in patients with breast or prostate cancers. For example, the VDR could be used in cancer biopsies as a diagnostic marker of invasiveness or, therapeutically, as a tumour suppressor. Potentially, drugs stabilizing or sensitizing the cytoplasmic VDR could be developed as adjuvant therapeutic targets.

Publications

• Loss of the Vitamin D Receptor in Breast Cancer Cells Enhances Bone Metastasis in a Murine Model of Breast Cancer. Asia-Pacific Journal of Clinical Oncology. Vol 10. 2014, Issue S7(Special Issue: SYDNEY CANCER CONFERENCE, 26 November 2014, The University of Sydney), pp. 11-27.
  Horas K, Zheng Y, Chow S, Fong-Yee C, Dunstan C, Zhou H, Seibel MJ
  
• Animal Models for Breast Cancer Metastasis to Bone: Opportunities and Limitations. Cancer investigation. 2015:1-10
  Horas K, Zheng Y, Zhou H, Seibel MJ
  (See online at https://doi.org/10.3109/07357907.2015.1065500)
• Loss of the vitamin D receptor in human breast and prostate cancers strongly induces cell apoptosis through downregulation of Wnt/β-catenin signaling. Bone Research, Vol. 5. 2017, Article number: 17023.
  Zheng Y., Trivedi T., Lin R.C., Fong-Yee C., Nolte R., Manibo J., Chen Y., Hossain M., Horas K., Dunstan C., Zhou H., Seibel M.J.
  (See online at https://doi.org/10.1038/boneres.2017.23)
• The Role of Vitamin D and the Vitamin D Receptor in Bone Oncology. Osteology/Osteologie. Vol. 27. 2018, Issue 3, pp. 129–134.
  Horas K., Holzapfel B.M., Jakob F., Kurth A.A., Maier G.S.
  (See online at https://dx.doi.org/10.1055/s-0038-1673534)
• Loss of the Vitamin D Receptor in Human Breast Cancer Cells Promotes Epithelial to Mesenchymal Cell Transition and Skeletal Colonization. Journal of Bone and Mineral Research, 2019 Apr 17.
  Horas K., Zheng Y., Fong-Yee C., Macfarlane E., Manibo J., Chen Y., Qiao J., Gao M., Haydar N., McDonald M.M., Croucher P.I., Zhou H., Seibel M.J.
  (See online at https://doi.org/10.1002/jbmr.3744)