Abstract P6-08-14: TRPS-1, a New GATA Family Transcription Factor, Regulates Epithelial-Mesenchymal Transition and Maintains an Estrogen Responsive, Claudin-Positive Phenotype in Breast Cancer Cells
| Autor: | Y. Bao, Jinyun Chen, Lg. Radvanyi, F Marincola, Yun Wu, X-H Leng, E Wang |
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| Rok vydání: | 2010 |
| Předmět: | |
| Zdroj: | Cancer Research. 70:P6-08 |
| ISSN: | 1538-7445 0008-5472 |
| Popis: | We recently reported that TRPS-1 (Trichorhinophalangeal Syndrome-1), a new GATA family transcription factor, is a ductal epithelial cell-specific gene expressed in normal breast and over-expressed in the majority of human breast cancer (BC), especially in ER+ BC. We also found that TRPS-1 is a marker for better prognosis when expressed over a critical threshold level using a new quantitative IHC method applied to over 150 primary BC cases of all subtypes. Here, we studied the molecular function of TRPS-1 using a lentiviral shRNA knockdown approach in an ER+ ductal epithelial BC cell line (T47D; luminal B type) normally expressing high levels of TRPS-1. Strikingly, knockdown of TRPS-1 in T47D cells resulted in a complete loss of epithelial markers, including E-cadherin and CK8/18 protein together with the loss of ER and a host of ER-associated genes, such as GATA-3 and FOXA1. In contrast, N-cadherin, vimentin, slug, and other genes associated with a mesenchymal phenotype were induced. Gene expression profiling using microarray found a number of additional differentially expressed genes following TRPS-1 knockdown, including a large decrease in the Prolactin receptor (PRLR), Claudin-1 and 6, EpCAM, PGR, and CD24, while AKT3 and MET (HGF-R) were increased. The Claudin-1 and PRLR gene were down-modulated 149-fold and 167-fold, respectively. This was verified at the protein level, with a total loss of cell surface Claudin-1 and PRLR expression in the TRPS-1 knockdown cells. Overall, the gene expression profile of TRPS-1 knockdown T47D cells resembled the recently described “Claudin-low” BC subset. TRPS-1 knockdown also had dramatic functional consequences, with the cells acquiring a mesenchymal, spindle-like morphology and high resistance to growth arrest and apoptosis under conditions of serum and estrogen deprivation. Moreover, these cells formed aggressive tumors in nude mice in an estrogen-independent manner after orthotopic injection into mammary fat pads, while control cells produced only small non-palpable tumors. In addition, transient induction of TRPS-1 expression in ER/TRPS-1-negative MDA-MB-231 cells led to a significant expression of ER together with other ER-associated genes. Our data suggests that TRPS-1 is a critical new GATA family transcription factor in the mammary gland that is at the hub of a cell lineage-determination pathway regulating epithelial-mesenchymal transition. In BC it may function in maintaining a more highly differentiated and less aggressive Claudin-positive ductal epithelial phenotype. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P6-08-14. |
| Databáze: | OpenAIRE |
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