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.
Subject(s)
Breast Neoplasms/metabolism , Breast Neoplasms/pathology , Drug Resistance, Neoplasm , Estrogen Antagonists/pharmacology , Peptides/metabolism , Animals , Antibodies , Antineoplastic Agents, Hormonal/pharmacology , Antineoplastic Agents, Hormonal/therapeutic use , Apoptosis , Blotting, Western , Breast Neoplasms/drug therapy , Breast Neoplasms/genetics , Cell Adhesion , Cell Line, Tumor , Cell Movement , Cell Proliferation , Estradiol/analogs & derivatives , Estradiol/pharmacology , Estradiol/therapeutic use , Female , Fulvestrant , Gene Expression , Gene Expression Regulation, Neoplastic , Humans , Mice , Mice, Inbred BALB C , Mice, Nude , Microarray Analysis , Neoplasm Invasiveness , Peptides/antagonists & inhibitors , Peptides/genetics , Prognosis , RNA, Small Interfering/genetics , Receptors, Estrogen/genetics , Receptors, Estrogen/metabolism , Reverse Transcriptase Polymerase Chain Reaction , Survival Rate , Tamoxifen/pharmacology , Tamoxifen/therapeutic use , Transplantation, Heterologous , Trefoil Factor-3ABSTRACT
The functional role of autocrine trefoil factor-1 (TFF1) in mammary carcinoma has not been previously elucidated. Herein, we demonstrate that forced expression of TFF1 in mammary carcinoma cells resulted in increased total cell number as a consequence of increased cell proliferation and survival. Forced expression of TFF1 enhanced anchorage-independent growth and promoted scattered cell morphology with increased cell migration and invasion. Moreover, forced expression of TFF1 increased tumor size in xenograft models. Conversely, RNA interference-mediated depletion of TFF1 in mammary carcinoma cells significantly reduced anchorage-independent growth and migration. Furthermore, neutralization of secreted TFF1 protein by polyclonal antibody decreased mammary carcinoma cell viability in vitro and resulted in regression of mammary carcinoma xenografts. We have therefore demonstrated that TFF1 possesses oncogenic functions in mammary carcinoma cells. Functional antagonism of TFF1 can therefore be considered as a novel therapeutic strategy for mammary carcinoma.
Subject(s)
Breast Neoplasms/metabolism , Carcinoma/metabolism , Tumor Suppressor Proteins/metabolism , Animals , Breast Neoplasms/pathology , Carcinoma/pathology , Cell Cycle , Cell Line, Tumor , Cell Movement , Cell Proliferation , Cell Survival , Disease Progression , Female , Humans , Mice , Mice, Inbred BALB C , Mice, Nude , Neoplasm Invasiveness , RNA Interference , RNA, Messenger/metabolism , Trefoil Factor-1 , Tumor Suppressor Proteins/immunologyABSTRACT
Trefoil factors (TFFs), in particular TFF1, are classical estrogen-regulated genes and have served as markers of estrogen gene regulation by various environmental estrogens. TFFs are also regulated by several other factors including growth hormone (hGH), insulin-like growth factor-1 (IGF-1), epidermal growth factor (EGF) and various oncogenic stimuli. TFFs are secreted proteins present in serum and possess the potential to act as growth factors promoting cell survival, anchorage-independent growth and motility. Recent compelling evidence has emerged from experimental and clinical studies to indicate a pivotal role of TFFs in oncogenic transformation, growth and metastatic extension of common human solid tumours. This review will summarize the current evidence for the involvement of TFFs in human cancer.
