title: Association between AXL, Hippo Transducers, and Survival Outcomes in Male Breast Cancer.
abstract: Male breast cancer (MBC) is an uncommon malignancy. We have previously reported that the expression of the Hippo transducers TAZ/YAP and their target CTGF was associated with inferior survival in MBC patients. Preclinical evidence demonstrated that Axl is a transcriptional target of TAZ/YAP. Thus, we herein assessed AXL expression to further investigate the significance of active TAZ/YAP-driven transcription in MBC. For this study, 255 MBC samples represented in tissue microarrays were screened for AXL expression, and 116 patients were included. The association between categorical variables was verified by the Pearson's Chi-squared test of independence (2-tailed) or the Fisher Exact test. The relationship between continuous variables was tested with the Pearson's correlation coefficient. The Kaplan-Meier method was used for estimating survival curves, which were compared by log-rank test. Factors potentially impacting 10-year and overall survival were verified in Cox proportional regression models. AXL was positively associated with the TAZ/CTGF and YAP/CTGF phenotypes (P = 0.001 and P = 0.002, respectively). Patients with TAZ/CTGF/AXL- or YAP/CTGF/AXL-expressing tumors had inferior survival compared with non-triple-positive patients (log rank P = 0.042 and P = 0.048, respectively). The variables TAZ/CTGF/AXL and YAP/CTGF/AXL were adverse factors for 10-year survival in the multivariate Cox models (HR 2.31, 95%CI:1.02-5.22, P = 0.045, and HR 2.27, 95%CI:1.00-5.13, P = 0.050). Nearly comparable results were obtained from multivariate analyses of overall survival. The expression pattern of AXL corroborates the idea of the detrimental role of TAZ/YAP activation in MBC. Overall, Hippo-linked biomarkers deserve increased attention in this rare disease. J. Cell. Physiol. 232: 2246-2252, 2017. © 2016 Wiley Periodicals, Inc.
authors.affiliation: Departmentof Pathology, "Regina Elena" National Cancer Institute, Rome, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Di Benedetto
authors.affiliation: Departmentof Pathology, "Regina Elena" National Cancer Institute, Rome, Italy.
authors.forename: Marcella
authors.initials: M
authors.lastname: Mottolese
authors.affiliation: Biostatistics-Scientific Direction, "Regina Elena" National Cancer Institute, Rome, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Sperati
authors.affiliation: Departmentof Pathology, "Regina Elena" National Cancer Institute, Rome, Italy.
authors.forename: Cristiana
authors.initials: C
authors.lastname: Ercolani
authors.affiliation: Division of Medical Oncology 2, "Regina Elena" National Cancer Institute, Rome, Italy.
authors.forename: Luigi
authors.initials: L
authors.lastname: Di Lauro
authors.affiliation: Division of Medical Oncology 2, "Regina Elena" National Cancer Institute, Rome, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Pizzuti
authors.affiliation: Division of Medical Oncology 2, "Regina Elena" National Cancer Institute, Rome, Italy.
authors.forename: Patrizia
authors.initials: P
authors.lastname: Vici
authors.affiliation: Biostatistics-Scientific Direction, "Regina Elena" National Cancer Institute, Rome, Italy.
authors.forename: Irene
authors.initials: I
authors.lastname: Terrenato
authors.affiliation: Department of Histopathology, Queen Elizabeth Hospital Birmingham and University of Birmingham, Birmingham, UK.
authors.forename: Abeer M
authors.initials: AM
authors.lastname: Shaaban
authors.affiliation: Leeds Institute of Cancer and Pathology, Wellcome Trust Brenner Building, University of Leeds, Leeds, UK.
authors.forename: Matthew P
authors.initials: MP
authors.lastname: Humphries
authors.affiliation: Leeds Institute of Cancer and Pathology, Wellcome Trust Brenner Building, University of Leeds, Leeds, UK.
authors.forename: Sreekumar
authors.initials: S
authors.lastname: Sundara-Rajan
authors.affiliation: Division of Medical Oncology 2, "Regina Elena" National Cancer Institute, Rome, Italy.|Scientific Direction, "Regina Elena" National Cancer Institute, Rome, Italy.
authors.forename: Maddalena
authors.initials: M
authors.lastname: Barba
authors.affiliation: Leeds Institute of Cancer and Pathology, Wellcome Trust Brenner Building, University of Leeds, Leeds, UK.
authors.forename: Valerie
authors.initials: V
authors.lastname: Speirs
authors.affiliation: Institute of General Pathology, Catholic University of the Sacred Heart, Largo Agostino Gemelli, Rome, Lazio, Italy.
authors.forename: Ruggero
authors.initials: R
authors.lastname: De Maria
authors.affiliation: Division of Medical Oncology 2, "Regina Elena" National Cancer Institute, Rome, Italy.|Scientific Direction, "Regina Elena" National Cancer Institute, Rome, Italy.
authors.forename: Marcello
authors.initials: M
authors.lastname: Maugeri-Saccà
mesh_terms: D000217:Acyltransferases; D048868:Adaptor Proteins, Signal Transducing / Q000032:analysis*; D000368:Aged; D014408:Biomarkers, Tumor / Q000032:analysis*; D018567:Breast Neoplasms, Male / Q000737:chemistry* / Q000401:mortality / Q000473:pathology; D016009:Chi-Square Distribution; D055513:Connective Tissue Growth Factor / Q000032:analysis; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D010750:Phosphoproteins / Q000032:analysis*; D011237:Predictive Value of Tests; D011379:Prognosis; D016016:Proportional Hazards Models; D011518:Proto-Oncogene Proteins / Q000032:analysis*; D020794:Receptor Protein-Tyrosine Kinases / Q000032:analysis*; D012189:Retrospective Studies; D012307:Risk Factors; D015398:Signal Transduction; D013997:Time Factors; D046888:Tissue Array Analysis; D014157:Transcription Factors / Q000032:analysis*; D000091102:YAP-Signaling Proteins; D000094963:Axl Receptor Tyrosine Kinase
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D014408:Biomarkers, Tumor; C526317:CCN2 protein, human; D010750:Phosphoproteins; D011518:Proto-Oncogene Proteins; D014157:Transcription Factors; D000091102:YAP-Signaling Proteins; C088374:YAP1 protein, human; D055513:Connective Tissue Growth Factor; D000217:Acyltransferases; C108675:TAFAZZIN protein, human; D020794:Receptor Protein-Tyrosine Kinases; D000094963:Axl Receptor Tyrosine Kinase; C000722289:AXL protein, human