title: Splicing factor ratio as an index of epithelial-mesenchymal transition and tumor aggressiveness in breast cancer.
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.
authors.affiliation: Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola (FC), Italy.
authors.forename: Pietro
authors.initials: P
authors.lastname: Fici
authors.affiliation: Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola (FC), Italy.
authors.forename: Giulia
authors.initials: G
authors.lastname: Gallerani
authors.affiliation: Inserm UMR-S1052, Centre de Recherche en Cancérologie de Lyon, Lyon, France.|CNRS UMR5286, Centre de Recherche en Cancérologie de Lyon, Lyon, France.|Centre Léon Bérard, Lyon, France.|UNIV UMR1052, Lyon, France.|Université de Lyon, Lyon, France.
authors.forename: Anne-Pierre
authors.initials: AP
authors.lastname: Morel
authors.affiliation: Osteoncology and Rare Tumors Center, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Mercatali
authors.affiliation: Osteoncology and Rare Tumors Center, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy.
authors.forename: Toni
authors.initials: T
authors.lastname: Ibrahim
authors.affiliation: Unit of Biostatistics and Clinical Trials, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, FC, Italy.
authors.forename: Emanuela
authors.initials: E
authors.lastname: Scarpi
authors.affiliation: Department of Medical Oncology, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, FC, Italy.
authors.forename: Dino
authors.initials: D
authors.lastname: Amadori
authors.affiliation: Inserm UMR-S1052, Centre de Recherche en Cancérologie de Lyon, Lyon, France.|CNRS UMR5286, Centre de Recherche en Cancérologie de Lyon, Lyon, France.|Centre Léon Bérard, Lyon, France.|UNIV UMR1052, Lyon, France.|Université de Lyon, Lyon, France.|Institut Universitaire de France, Paris, France.
authors.forename: Alain
authors.initials: A
authors.lastname: Puisieux
authors.affiliation: Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola (FC), Italy.
authors.forename: Michel
authors.initials: M
authors.lastname: Rigaud
authors.affiliation: Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola (FC), Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Fabbri
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017398:Alternative Splicing; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008875:Middle Aged; D060787:Neoplasm Grading; D011379:Prognosis; D000072260:RNA Splicing Factors / Q000235:genetics / Q000378:metabolism*; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D014408:Biomarkers, Tumor; C539364:ESRP1 protein, human; C539365:ESRP2 protein, human; C454924:RBFOX2 protein, human; D000072260:RNA Splicing Factors; D016601:RNA-Binding Proteins; D012097:Repressor Proteins
keywords: EMT; EMT ratio; alternative splicing; early breast cancer; tumor aggressiveness