Abstract
Epithelial-mesenchymal transition (EMT) in cancer cells plays a pivotal role in determining metastatic prowess, but knowledge of EMT regulation remains incomplete. In this study, we defined a critical functional role for the Forkhead transcription factor FOXQ1 in regulating EMT in breast cancer cells. FOXQ1 expression was correlated with high-grade basal-like breast cancers and was associated with poor clinical outcomes. RNAi-mediated suppression of FOXQ1 expression in highly invasive human breast cancer cells reversed EMT, reduced invasive ability, and alleviated other aggressive cancer phenotypes manifested in 3-dimensional Matrigel (BD Biosciences) culture. Conversely, enforced expression of FOXQ1 in differentiated human mammary epithelial cells (HMLER) or epithelial cancer cell lines provoked an epithelial to mesenchymal morphologic change, gain of stem cell-like properties, and acquisition of resistance to chemotherapy-induced apoptosis. Mechanistic investigations revealed that FOXQ1-induced EMT was associated with transcriptional inactivation of the epithelial regulator E-cadherin (CDH1). Our findings define a key role for FOXQ1 in regulating EMT and aggressiveness in human cancer.
Highlights
Metastasis of tumor cells to distant organs is the most common cause of death arising from human carcinomas
The results show that FOXQ1 was consistently expressed in higher levels in aggressive breast cancer cells than that in nonaggressive breast cancer cells (Fig. 1B)
FOXQ1 expression is correlated with most of the colon carcinoma cell lines, and ectopic expression FOXQ1 in one of the FOXQ1-deficient epithelial carcinoma cell induce Epithelial-mesenchymal transition (EMT) and make these cells become drug resistant. These results suggest FOXQ1 is envisioned to play a role in the progression of breast cancer in patients, as well as exert functional impact in colon carcinoma
Summary
Metastasis of tumor cells to distant organs is the most common cause of death arising from human carcinomas. Carcinoma cells often activate a transdifferentiation step known as epithelial-mesenchymal transition (EMT), a dynamic cellular process thought to underlie metastasis by promoting acquisition of migratory and invasive abilities [1, 2]. On downregulation of E-cadherin, epithelial cells acquire a fibroblastic phenotype, dissociate from the epithelium, and migrate. Several proteins have been identified that can downregulate E-cadherin expression including SNAIL, SLUG, Authors' Affiliations: 1Cancer Biology and Pharmacology and 2Information and Mathematical Science, Genome Institute of Singapore, A*STAR (Agency for Science, Technology and Research), Biopolis; 3Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore; and 4Cancer and Stem Cell Biology, DUKE-NUS Graduate Medical School of Singapore, Singapore, Singapore
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