|Title:||Identification of a Novel Ligand Independent Function of the Cytoplasmic Vitamin D Receptor in Breast Cancer|
|Publisher:||Faculty of Medicine.|
Concord Clinical School.
University of Sydney.
|Abstract:||This thesis aims to define the role of the vitamin D receptor (VDR) in breast cancer (BC), hypothesising that in contrast to the anti-proliferative effects of its ligand, 1.25-dihydroxy vitamin D3, VDR knockdown would enhance BC cell growth. Using stable shRNA expression, VDR expression was knocked down (VDR-KD) in two human BC cell lines, namely MDA-Tx-SA and MCF-7 cells. Parental (PA) and non-target (shNT) cells served as controls. In ligand-free culture, VDR-KD significantly reduced BC cell growth and induced cell apoptosis. In vivo, VDR-KD suppressed BC cell growth in both the mammary fat pad and the bone environment. However, VDR-KD cells exhibited increased invasive potential, likely via changes in beta-catenin and E-cadherin signaling. These findings suggest a ligand-independent effect of the VDR on BC cell behaviour. Transfection of VDR-KD BC cells with a mutant VDR construct unable to translocate to the nucleus restored normal growth of VDR-KD BC cells. I conclude that in contrast to the known anti-proliferative actions of the liganded VDR, the cytoplasmic VDR promotes BC cell growth. This discovery adds to our understanding of VDR signaling in BC and may help to resolve discrepancies regarding the association between vitamin D status and BC prognosis.|
|Access Level:||Access is restricted to staff and students of the University of Sydney . UniKey credentials are required. Non university access may be obtained by visiting the University of Sydney Library.|
|Rights and Permissions:||The author retains copyright of this thesis. It may only be used for the purposes of research and study. It must not be used for any other purposes and may not be transmitted or shared with others without prior permission.|
|Type of Work:||PhD Doctorate|
|Type of Publication:||Doctor of Philosophy Ph.D.|
|Appears in Collections:||Sydney Digital Theses (University of Sydney Access only)|
|Trupti TRIVEDI - Final thesis.pdf||6.5 MB||Adobe PDF|
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