@article{97b3ff3482a144c7813bc5b21e552855,
title = "Trefoil factor 3 is oncogenic and mediates anti-estrogen resistance in human mammary carcinoma",
abstract = "We report herein that trefoil factor 3 (TFF3) is oncogenic and mediates anti-estrogen resistance in human mammary carcinoma. Forced expression of TFF3 in mammary carcinoma cells increased cell proliferation and survival, enhanced anchorage-independent growth, and promoted migration and invasion. Moreover, forced expression of TFF3 increased tumor size in xenograft models. Conversely, depletion of endogenous TFF3 with small interfering RNA (siRNA) decreased the oncogenicity and invasiveness of mammary carcinoma cells. Neutralization of secreted TFF3 by antibody promoted apoptosis, decreased cell growth in vitro, and arrested mammary carcinoma xenograft growth. TFF3 expression was significantly correlated to decreased survival of estrogen receptor (ER)-positive breast cancer patients treated with tamoxifen. Forced expression of TFF3 in mammary carcinoma cells increased ER transcriptional activity, promoted estrogen-independent growth, and produced resistance to tamoxifen and fulvestrant in vitro and to tamoxifen in xenograft models. siRNA-mediated depletion or antibody inhibition of TFF3 significantly enhanced the efficacy of antiestrogens. Increased TFF3 expression was observed in tamoxifen-resistant (TAMR) cells and antibody inhibition of TFF3 in TAMR cells improved tamoxifen sensitivity. Functional antagonism of TFF3 therefore warrants consideration as a novel therapeutic strategy for mammary carcinoma.",
author = "Nagarajan Kannan and Ian Kang and Xiangjun Kong and Jianzhong Tang and Perry, {Jo K.} and Mohankumar, {Kumarasamypet M.} and Miller, {Lance D.} and Liu, {Edison T.} and Mertani, {Hichem C.} and Tao Zhu and Grandison, {Prudence M.} and Liu, {Dong Xu} and Lobie, {Peter E.}",
note = "Funding Information: Abbreviations: BrdU, bromodeoxyuridine; CS-FBS, charcoal-stripped fetal bovine serum; DMFS, distant metastasis-free survival; ER, estrogen receptor; qPCR, quantitative polymerase chain reaction; siRNA, small interfering RNA; TFF3, trefoil factor 3; TFF3-pAb, TFF3-polyclonal antibody Address all correspondence to: Peter E. Lobie, MD, PhD, Cancer Science Institute of Singapore, National University of Singapore, Centre for Life Sciences, #03-06C, 28 Medical Dr, Singapore 117456. E-mail: csipel@nus.edu.sg 1This work was funded by the Breast Cancer Research Trust (NZ), the Foundation for Research, Science and Technology of New Zealand, the Cancer Science Institute of Singapore, the Hundred-Talent Scheme of Chinese Academy of Sciences, National Natural Science Foundation of China (30571030), and National Basic Research Program of China (2007CB914503). 2N.K., J.K., X.G.K., J.Z.T., J.K.P., M.K.M., L.D.M., E.T.L., H.C.M., P.M.G., and D.X.L. have no conflicts of interest to declare. P.E.L. and T.Z. consult for and P.E.L. has equity interest in Perseis Therapeutics Ltd. P.E.L. is also named on PCT application numbers WO 2006/69253 and WO 2008/042435 and US provisional application number 61/059558. 3This article refers to supplementary materials, which are designated by Tables W1 to W3 and Figures W1 to W6 and are available online at www.neoplasia.com. 4Current address: Terry Fox Laboratory, British Columbia Cancer Research Centre, 675 W 10th Ave, Vancouver, Canada V5Z 1L3. 5These authors contributed equally to this work. 6Current address: Department of Developmental Neurobiology, St Jude Children{\textquoteright}s Research Hospital, Memphis, TN. Received 29 June 2010; Revised 12 August 2010; Accepted 24 August 2010 Copyright {\textcopyright} 2010 Neoplasia Press, Inc. All rights reserved 1522-8002/10/$25.00 DOI 10.1593/neo.10916",
year = "2010",
month = dec,
doi = "10.1593/neo.10916",
language = "English (US)",
volume = "12",
pages = "1041--1053",
journal = "Neoplasia",
issn = "1522-8002",
publisher = "Elsevier Inc.",
number = "12",
}