Deficiency in trefoil factor 1 (TFF1) increases tumorigenicity of human breast cancer cells and mammary tumor development in TFF1-knockout mice

Abstract

Although trefoil factor 1 (TFF1; previously named pS2) is abnormally expressed in about 50% of human breast tumors, its physiopathological role in this disease has been poorly studied. Moreover, controversial data have been reported. TFF1 function in the mammary gland therefore needs to be clarified. In this study, using retroviral vectors, we performed TFF1 gain- or loss-of-function experiments in four human mammary epithelial cell lines: normal immortalized TFF1-negative MCF10A, malignant TFF1-negative MDA-MB-231 and malignant TFF1-positive MCF7 and ZR75.1. The expression of TFF1 stimulated the migration and invasion in the four cell lines. Forced TFF1 expression in MCF10A, MDA-MB-231 and MCF7 cells did not modify anchorage-dependent or -independent cell proliferation. By contrast, TFF1 knockdown in MCF7 enhanced soft-agar colony formation. This increased oncogenic potential of MCF7 cells in the absence of TFF1 was confirmed in vivo in nude mice. Moreover, chemically induced tumorigenesis in TFF1-deficient (TFF1-KO) mice led to higher tumor incidence in the mammary gland and larger tumor size compared with wild-type mice. Similarly, tumor development was increased in the TFF1-KO ovary and lung. Collectively, our results clearly show that TFF1 does not exhibit oncogenic properties, but rather reduces tumor development. This beneficial function of TFF1 is in agreement with many clinical studies reporting a better outcome for patients with TFF1-positive breast primary tumors.

Análise De Expressão Gênica Na Identificação De Potenciais Marcadores Preditivos Em Neoplasias Malignas Mamárias

“…Os resultados da Análise 2, realizada no presente estudo (neoplasia maligna primária e linfonodos correspondentes), demonstraram que dos seis genes avaliados (SERPINA1, TFF3, TFF1, ARD1A, NGX6 e DKK1), apenas o gene TFF1 apresentou expressão diferencial significativa. O gene TFF1 é um gene constitutivo e altamente expresso no tecido do trato gastrointestinal, onde desempenha um importante papel na diferenciação das glândulas gástricas e, também, na proteção da camada mucosa gástrica (BUACHE et al, 2011;MARKICEVIC et al, 2014). Além disso, esse gene também apresenta expressão diferenciada em cânceres, como os de pulmão, ovário, mama, intestino e outras neoplasias (BUACHE et al, 2011;MARKICEVIC et al, 2014).…”

SUMOylation and SUMO-interacting Motif (SIM) of Metastasis Tumor Antigen 1 (MTA1) Synergistically Regulate Its Transcriptional Repressor Function

“…Overexpression of MTA1 in breast cancer cells significantly enhances the invasive ability of these cells to invade in an anchorage-independent manner by reducing the levels of ER target genes, including PS2 (10). A recent study reports that a deficiency of PS2 increases the tumorigenicity of human breast cancer cells and mammary tumor development in PS2 knock-out mice (37). Therefore, our study of the expression of SUMO2 being up-regulated by MTA1 provides a clue that MTA1 may contribute to the metastatic ability of cells by modulating the SUMOylation pathway, which in turn regulates the repressive effect of MTA1 on its target gene, e.g.…”

Metabolomics and Transcriptional Responses in Estrogen Receptor Positive Breast Cancer Cells

“…Interestingly, MSK activation by TPA in MCF-7 cells induces H3S10 phosphorylation but not H3S28 phosphorylation by an unknown mechanism (Espino et al, 2006). However, a recent study has called into question the value of using TFF1 as a prognostic marker in breast cancer, as it demonstrates that knockdown of TFF1 in MCF-7 cells leads to enhanced colony formation in soft agar, and that TFF1 knock-out mice have a higher tumor incidence in mammary glands (Buache et al, 2011). In the ER-MDA-MB-231 and SKBR-3 cells, MSK is implicated in the expression of the proinflammatory cytokine IL-6, whereby IL-6 is constitutively expressed and MSK is recruited to the IL-6 promoter following TNF-signaling.…”