Programme(s) to which this project applies:
|☒ MPhil/PhD||☑ MRes[Med]||☒ URIS|
Objective and Significance:
Breast cancer is the commonest female cancer. Endocrine therapy is given to estrogen-receptor positive (ER+) breast cancer patients to inhibit disease progression. Androgen receptor (AR) is widely expressed in breast cancer, and has become increasingly important as a potential therapeutic target.
BQ323636.1 (BQ in short) is a novel splice-variant to nuclear co-repressor-2 (NCOR2). BQ overexpression is a predictor for tamoxifen resistance in ER-positive breast cancer and also contributes to cytotoxic-drug resistance. BQ overexpression compromises the suppressive role of NCOR2, rescuing transcriptional suppression of target genes, leading to tamoxifen- and chemo-resistance.
ARv7 is an AR splice-variant that lacks the ligand-binding domain, rendering it constitutively active. In prostate cancer ARv7 is associated with therapy resistance and poor clinical outcome. Its significance in breast cancer is unclear. We hypothesize that androgen response activity in governed by both wildtype AR and splice-variant ARv7 in contributing to chemoresistance, with BQ further modulating its response.
Research Plan and Methodology:
Breast cancer cell lines MCF-7, MDA-MB-231 and MDA-MB-453 and their stable BQ-overexpressing counterparts will be used for in vitro study. Cell viability, clonogenic and luciferase reporter assays, and cell cycle analysis will be employed. Xenograft mouse model will also be used. The effect of BQ on the activity of wild-type AR (ARfl) and ARv7 and on doxorubicin response in breast cancer will be investigated in vitro and in vivo. As simply assessing AR expression may not be indicative of AR activity, we propose to assess BQ/ARv7/AR in breast cancer in tissue microarray by immunohistochemistry, correlating the results with clinical outcome and doxorubicin resistance.
Through investigating the mechanism of action of ARv7 and BQ and their contribution doxorubicin resistance, the controversial role of AR may be better clarified. AR expression status alone may not be sufficient to guide adjuvant therapy. The outcomes of this project will contribute new insights into the mechanisms behind acquired chemoresistance and may significantly impact breast cancer management.
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