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Professor KHOO Ui Soon | uskhoo@pathology.hku.hk
Professor
MBBCh BAO Irel; MD HK; MMedSc (Path) Irel; FRCPath UK; FHKCPath; MIAC;
FHKAM; (Pathology)

Ada M.F. Chan Professor in Oncological Pathology

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 studies have shown that sustained nuclear FOXO3a expression is linked with uncoupling of the Akt-FOXO3a signaling axis and is associated with poor survival in invasive breast cancer. In collaboration with clinical oncologists we have established our own breast cancer tissue microarray (TMA) of Chinese breast cancer patients with 10 year clinical follow up data. These TMAs have facilitated productive collaboration with basic scientists unraveling the contribution of FOXO3a, the Akt-FOXO3a signaling axis and its relation with FOXM1, SIRT6 and VEGF in the development of chemotherapeutic resistance in breast cancer.

Using custom designed splice array to investigate the pattern of splice-variants, we identified a novel splice variant (BQ323636.1) of the nuclear receptor co-repressor 2 (NCOR2) gene that was associated with tamoxifen resistance. This BQ variant lacks a phosphorylation site responsible for proteasome-mediated degradation of NCOR2, rendering it more resistant to degradation, thus competing with NCOR2 for binding to protein partners. Supported by an Innovation Technology Fund grant, we have generated a BQ-specific antibody to further our investigation in this area. In an International collaborative study with Nottingham, we found nuclear BQ overexpression a robust biomarker, highly significantly associated with tamoxifen resistance, cancer metastasis, disease relapse and poorer overall and disease-specific survival. 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. Our ultimate plan is to develop its use as targeted therapy for tamoxifen resistant breast cancer patients. We have obtained US Provisional Patent (IP00577) with a PTC application filed and published.

Nothing is known of what controls the expression of BQ. We are currently investigating upstream pathways and genomic aberrations in splicosome genes that may give rise to other novel splice variants which could lead to tamoxifen resistance. The identification of the factors regulating its expression would provide insights to the future design of potential therapeutic targets to combat tamoxifen resistance. Other ongoing studies include Genome-Wide Association Studies (GWAS) as part of the Asian Breast Consortium.

Major Research Grants

Patents

US provisional patent (IP00577) “The use of anti-BQ323636.1 monoclonal antibody for predicting breast cancer patients’ tamoxifen response status.” PTC Application Filed August 30th 2016.

Awards and Honors

Medical Education

Community Service

Selected Publications

Click here for detailed publication list

Researcher Profile on HKU Scholars Hub

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. doi: 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. doi: 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. doi: 10.1038/onc.2015.152.

Gong C, Fujino K, Monteiro LJ, Gomes AR, Drost R, Takeda S, Khoo US, Jonkers J, Sprou D, Lam EW. FOXA1 repression is associated with loss of BRCA1 and increased promoter methylation and silencing in breast cancer. Oncogene. 2015 34(39): 5012-24. doi: 10.1038/onc.2014.421

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. doi: 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. doi: 10.1093/carcin/bgt098. (*corresponding authors)

Karadedou CT, Gomes AR, Chen J, Petkovic M, Ho KK, Zwolinska AK, Feltes A, Wong SY, Chan KY, Cheung YN, Tsang JW, Brosens JJ, Khoo US, Lam EW. FOXO3a represses VEGF expression through FOXM1-dependent and -independent mechanisms in breast cancer. Oncogene. 2012 Apr 5;31(14):1845-58. doi: 10.1038/onc.2011.368. Epub 2011 Aug 22.

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.