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.
authors.affiliation: Liggins Institute, University of Auckland, Auckland, New Zealand.
authors.forename: Nagarajan
authors.initials: N
authors.lastname: Kannan
authors.forename: Jian
authors.initials: J
authors.lastname: Kang
authors.forename: Xiangjun
authors.initials: X
authors.lastname: Kong
authors.forename: Jianzhong
authors.initials: J
authors.lastname: Tang
authors.forename: Jo K
authors.initials: JK
authors.lastname: Perry
authors.forename: Kumarasamypet M
authors.initials: KM
authors.lastname: Mohankumar
authors.forename: Lance D
authors.initials: LD
authors.lastname: Miller
authors.forename: Edison T
authors.initials: ET
authors.lastname: Liu
authors.forename: Hichem C
authors.initials: HC
authors.lastname: Mertani
authors.forename: Tao
authors.initials: T
authors.lastname: Zhu
authors.forename: Prudence M
authors.initials: PM
authors.lastname: Grandison
authors.forename: Dong-Xu
authors.initials: DX
authors.lastname: Liu
authors.forename: Peter E
authors.initials: PE
authors.lastname: Lobie
mesh_terms: D000818:Animals; D000906:Antibodies; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D019008:Drug Resistance, Neoplasm; D004958:Estradiol / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D004965:Estrogen Antagonists / Q000494:pharmacology*; D005260:Female; D000077267:Fulvestrant; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D046228:Microarray Analysis; D009361:Neoplasm Invasiveness; D010455:Peptides / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011379:Prognosis; D034741:RNA, Small Interfering / Q000235:genetics; D011960:Receptors, Estrogen / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015996:Survival Rate; D013629:Tamoxifen / Q000494:pharmacology / Q000627:therapeutic use; D014183:Transplantation, Heterologous; D000071165:Trefoil Factor-3
chemical_list: D000906:Antibodies; D018931:Antineoplastic Agents, Hormonal; D004965:Estrogen Antagonists; D010455:Peptides; D034741:RNA, Small Interfering; D011960:Receptors, Estrogen; C082495:TFF3 protein, human; D000071165:Trefoil Factor-3; D013629:Tamoxifen; D000077267:Fulvestrant; D004958:Estradiol