Department of Pathology

Research Topic

Molecular oncology, pathology and genetics of breast cancer

Research Description

My research interests focuses on investigating the underlying molecular mechanisms contributing towards drug resistance in the treatment of breast cancer. This includes cancer genetics, biomarker identification and the development of novel targeted therapies. It is a multidisciplinary endeavor aimed at integrating basic science research with clinical and translational studies for the development of new therapeutics and involves the contribution of basic scientists and clinicians from various disciplines.

Our team identified BQ323636.1, a novel splice variant to the NCOR2 gene associated with tamoxifen resistance and raised a monoclonal antibody targeting the epitope unique to this variant, which has been shown to be a robust biomarker to predict tamoxifen resistance and for which a Patent Cooperation Treaty has been filed. In this way more appropriate alternative therapy can be given at an early stage which can save patients from the side effects/risks of inappropriate treatment by tamoxifen. BQ can bind to NCOR2, forming a defective co-repressor complex for suppression of transcription factor signaling. More recently, we found BQ overexpression enhanced antioxidant genes expression by upregulating NRF2 transcriptional activity on the antioxidant-response element, leading to cytotoxic drug resistance in breast cancer. We are also investigating its role in conferring Aromatase Inhibitor resistance in post-menopausal women with estrogen receptor positive breast cancer.

We also developed a multidisciplinary platform making use of Ivabradine, an FDA approved HCN (Hyperpolarization-activated cyclic nucleotide-gated channel) blocker used clinically to treat chronic angina, to effectively suppress breast cancer growth without the side-effects produced by conventional chemotherapeutic agents. Provisional patent has been filed for the novel use of Ivabradine particularly as treatment for triple negative breast cancer, as well as other types of cancer. Our long term goal is to translate these areas of research into clinical trials, thus bridging the gap between laboratory and the clinics for the benefit of patients in Hong Kong and worldwide.

Research Grants

RGC - Competitive Earmarked Research Grants 2020, 2007, 2006, 2005
CGDN - Canadian Genetic Diseases Network Grant 2004
HMRF –Health & Medical Research Fund 2020, 2019, 2017
ITF – Innovation and Technology Fund 2013, 2017
RFCID – Research Fund of the Control of Infectious Diseases 2004, 2005, 2006
SK Yee Medical Foundation 2010, 2013

Patents

US national stage of International Patent Application (UHK.198X). A Monoclonal Antibody for Predicting Tamoxifen Response in Breast Cancer Patients. Filed May 25, 2018
China national stage of International Patent Application (CPCH1860337P). A Monoclonal Antibody for Predicting Tamoxifen Response in Breast Cancer Patients. Filed April 17, 2018
Patent Cooperation Treaty (PTC/CN2016/097131) A Monoclonal Antibody for Predicting Tamoxifen Response in Breast Cancer Patients. Filed November 2016
Patent Cooperation Treaty (PTC/CN2018/084417) “Use of HCN Inhibitors for Treatment of Cancer” Filed April 2018

Awards and Honors

Ada MF Chan Endowed Professor in Oncologic Pathology (2017)
Croucher Senior Research Fellowship Award (2015) https://scholars.croucher.org.hk/scholars/ui-soon-khoo; https://projects.croucher.org.hk/news/the-how-and-why-cancer-pathology
Faculty Teaching Medal, The University of Hong Kong (2007)
Vice-Chancellor Grant, The University of Hong Kong (1997)
Mary Sun Fellowship in Oncology (1993)
Fellowship Grant, Medical Research Council of Ireland. (1982)
Medical Faculty Scholarship and Prize in Experimental Medicine, University College Galway (1980)

Education

Chairman, Departmental Teaching Committee
Academic Director, Master in Molecular and Diagnostic Pathology (MMDPath)
Member, Peer Review Panel on Teaching

Community Service

Executive Council member, International Academy of Cytology (2013 - 2016)
President, Hong Kong Society of Cytology (2008 - 2010)
Honorary Treasurer, Hong Kong Museum of Medical Sciences (2008 - 2011)

Selected Publications

Click here for detailed publication list

Researcher Profile on HKU Scholars Hub

Gong C, Tsoi H, Mok KC, Cheung J, Man, EPS, Fujino K, Wong A, Lam EWF, Khoo US. Phosphorylation independent eIF4E translational reprogramming of selective mRNAs determines tamoxifen resistance in breast cancer. Oncogene 2020 Feb 17; https://doi.org/10.1038/s41388-020-1210-y.

Blog post in Nature Research Cancer Community:
https://cancercommunity.nature.com/users/354911-ui-soon-khoo/posts/59676-rethinking-the-role-of-translational-reprogramming-in-the-development-of-tamoxifen-resistant-breast-cancer

Leung MH, Tsoi H, Gong C, Man EPS, Zona S, Yao S, Lam EWF, Khoo US. A Splice Variant of NCOR2, BQ323636.1, Confers Chemoresistance in Breast Cancer by Altering the Activity of NRF2. Cancers 2020 12(3), 533; https://doi.org/10.3390/cancers12030533

Gong C, Man EP, Tsoi H, Lee TK, Lee P, Mak ST, Wong LS, Luk MY, Rakha EA, Green AR, Ellis IO, Lam EW, Cheung KL, Khoo US. BQ323636.1, a Novel Splice Variant to NCOR2, as a Predictor for Tamoxifen Resistant Breast Cancer. Clin Cancer Res. 2018 Aug 1; 24 (15): 3480-3482. https://doi.org/10.1158/1078-0432.CCR-18-0759

An L, Jiang Y, Ng HH, Man EP, Chen J, Khoo US*, Gong Q*, Huen MS*. Dual-utility NLS drives RNF169-dependent DNA damage responses. Proc Natl Acad Sci U S A. 2017 Mar 21. pii: 201616602. https://doi.org/10.1073/pnas.1616602114 (*corresponding authors)

Gong C, Yao S, Gomes AR, Man EP, Lee HJ, Gong G, Chang S, Kim SB, Fujino K, Kim SW, Park SK, Lee JW, Lee MH; KOHBRA study group, Khoo US*, Lam EW*. BRCA1 positively regulates FOXO3 expression by restricting FOXO3 gene methylation and epigenetic silencing through targeting EZH2 in breast cancer. Oncogenesis. 2016 Apr 4;5:e214.

https://doi.org/10.1038/oncsis.2016.23 (*corresponding authors)

Khongkow P, Gomes AR, Gong C, Man EPS, Tsang JWH, Fung J, Monteiro LJ, Medema RH, Khoo US, Lam EWF. Paclitaxel targets FOXM1 to regulate KIF20A in mitotic catastrophe and breast cancer paclitaxel resistance. Oncogene. 2016 35(8): 990-1002.

https://doi.org/10.1038/onc.2015.152

Zhang L, Gong C, Lau SL, Yang N, Wong OG, Cheung AN, Tsang JW, Chan KY, Khoo US. SpliceArray profiling of breast cancer reveals a novel variant of NCOR2/SMRT that is associated with tamoxifen resistance and control of ERα transcriptional activity. Cancer Res. 2013 Jan 1;73(1):246-55.
https://doi.org/10.1158/0008-5472.CAN-12-2241

Khongkow M, Olmos Y, Gong C, Gomes AR, Monteiro LJ, Yagüe E, Cavaco TB, Khongkow P, Man EP, Laohasinnarong S, Koo CY, Harada-Shoji N, Tsang JW, Coombes RC, Schwer B, Khoo US*, Lam EW*. SIRT6 modulates paclitaxel and epirubicin resistance and survival in breast cancer. Carcinogenesis. 2013 34(7):1476-86. https://doi.org/10.1093/carcin/bgt098 (*corresponding authors)

Chen J, Gomes AR, Monteiro LJ, Wong SY, Wu LH, Ng TT, Karadedou CT, Millour J, Ip YC, Cheung YN, Sunters A, Chan KY, Lam EW, Khoo US. Constitutively nuclear FOXO3a localization predicts poor survival and promotes Akt phosphorylation in breast cancer. PLoS One. 2010 Aug 20;5(8). pii: e12293.

Chan KY, Liu W, Long JR, Yip SP, Chan SY, Shu XO, Chua DTT, Cheung ANY, Ching JCY, Cai H, Au GHK, Chan M, Foo W, Ngan HYS, Gao YT, Ngan ESW, Garcia-Barcelo MM, Zheng W, Khoo US. Functional polymorphisms in the promoter of BRCA1 influence transcription and are associated with decreased risk for breast cancer in Chinese women. J Med Genet. 2009; 46, 32-39

Chen YX, Chan VSF, Zheng BJ, Chan KY, To YF, Khoo US, Lin CL. A novel subset of putative lung stem/progenitor CD34+Oct-4+ cells is the major target for SARS coronavirus in human lung. J Exp Med, 2007: 204(11); 2529-2536

Chan VS, Chan KY, Chen Y, Poon LL, Cheung AN, Zheng B, Chan KH, Mak W, Ngan HY, Xu X, Screaton G, Tam PK, Austyn JM, Chan LC, Yip SP, Peiris M, Khoo US*, Lin CL*. (*corresponding authors) Homozygous L-SIGN (CLEC4M) plays a protective role in SARS coronavirus infection. Nat Genet 2006; 38(1):38-46.

Chan KY, Ozcelik H, Cheung AN, Ngan HY, Khoo US. Epigenetic factors controlling the BRCA1 and BRCA2 genes in sporadic ovarian cancer. Cancer Res. 2002;62(14):4151-6

Khoo US, Chan KY, Cheung AN, Xue WC, Shen DH, Fung KY, Ngan HY, Choy KW, Pang CP, Poon CS, Poon AY, Ozcelik H. Recurrent BRCA1 and BRCA2 germline mutations in ovarian cancer: a founder mutation of BRCA1 identified in the Chinese population. Hum Mutat. 2002;19(3):307-8.

Chan KY, Cheung AN, Yip SP, Ko HH, Lai TW, Khoo US. Population-based case-control study of HER2 genetic polymorphism and breast cancer risk. J Natl Cancer Inst. 2002;94(20):1581-2.

Khoo US, Ngan HY, Cheung AN, Chan KY, Lu J, Chan VW, Lau S, Andrulis IL, Ozcelik H. Mutational analysis of BRCA1 and BRCA2 genes in Chinese ovarian cancer identifies 6 novel germline mutations. Hum Mutat. 2000;16(1):88-9.

Khoo US, Ozcelik H, Cheung AN, Chow LW, Ngan HY, Done SJ, Liang AC, Chan VW, Au GK, Ng WF, Poon CS, Leung YF, Loong F, Ip P, Chan GS, Andrulis IL, Lu J, Ho FC. Somatic mutations in the BRCA1 gene in Chinese sporadic breast and ovarian cancer. Oncogene. 1999;12;18(32):4643-6.