Oncotarget

Research Papers:

Splicing factor ratio as an index of epithelial-mesenchymal transition and tumor aggressiveness in breast cancer

Pietro Fici _, Giulia Gallerani, Anne-Pierre Morel, Laura Mercatali, Toni Ibrahim, Emanuela Scarpi, Dino Amadori, Alain Puisieux, Michel Rigaud and Francesco Fabbri

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Oncotarget. 2017; 8:2423-2436. https://doi.org/10.18632/oncotarget.13682

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Abstract

Pietro Fici1, Giulia Gallerani1, Anne-Pierre Morel2,3,4,5,6, Laura Mercatali7, Toni Ibrahim7, Emanuela Scarpi8, Dino Amadori9, Alain Puisieux2,3,4,5,6,10, Michel Rigaud1, Francesco Fabbri1

1Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola (FC), Italy

2Inserm UMR-S1052, Centre de Recherche en Cancérologie de Lyon, Lyon, France

3CNRS UMR5286, Centre de Recherche en Cancérologie de Lyon, Lyon, France

4Centre Léon Bérard, Lyon, France

5UNIV UMR1052, Lyon, France

6Université de Lyon, Lyon, France

7Osteoncology and Rare Tumors Center, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy

8Unit of Biostatistics and Clinical Trials, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, FC, Italy

9Department of Medical Oncology, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, FC, Italy

10Institut Universitaire de France, Paris, France

Correspondence to:

Pietro Fici, email: [email protected]

Keywords: EMT, early breast cancer, tumor aggressiveness, alternative splicing, EMT ratio

Received: May 10, 2016     Accepted: November 21, 2016     Published: November 29, 2016

ABSTRACT

Epithelial-to-mesenchymal transition (EMT) has been shown to be associated with tumor progression and metastasis. During this process in breast cancer, a crucial role is played by alternative splicing systems. To identify a new early prognostic marker of metastasis, we evaluated EMT-related gene expression in breast cell lines, and in primary tumor tissue from 31 patients with early breast cancer, focusing our attention on EMT-related splicing factors ESRP1, ESRP2 and RBFOX2. Results showed that the expression patterns of these genes were indicative of the onset of EMT in in-vitro models, but not in tissue samples. However, the ratio between ESRP1 or ESRP2 and RBFOX2 significantly decreased during EMT and positively correlated with the EMT-specific phenotype in cell models, representing a promising prognostic markers. Low ESRP1/RBFOX2 ratio value was associated with a higher risk of metastasis (p < 0.005) in early breast cancer patients, regardless other clinical features. A cut-off of ratio of 1.067 was determined by ROC curve analysis (AUC 0.8375; 95% CI 0.6963–0.9787). Our study show evidence that a decrease in this ratio correlates with cancer progression. The results provide a rationale for using ESRP1/RBFOX2 ratio as a new prognostic biomarker for the early prediction of metastatic potential in breast cancer.


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