Research Projects
Molecular Biology of Endocrine-Resistant/Chemo-Resistant Breast Cancer


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.

Professor US Khoo, Department of Pathology

Biography
uskhoo@hku.hk

For more information or to express interest for this project, please email the supervisor or the specified contact point in the project description.  Interested candidates are advised to enclose with your email:

  1. your CV,
  2. a brief description of your research interest and experience, and
  3. two reference letters (not required for HKUMed UG students seeking MRes[Med]/URIS projects).

Information on the research programme, funding support and admission documentations could be referenced online at the Research Postgraduate Admissions website. General admission enquiries should be directed to rpgmed@hku.hk.

HKUMed MBBS students interested in the Master of Research in Medicine (MRes[Med]) programme may visit the programme website for more information.  

HKUMed UG students interested in the Undergraduate Research Internship Scheme (URIS) may visit the scheme’s website for more information. 

Research @ Department of Pathology