title: The Hippo transducers TAZ/YAP and their target CTGF in male breast cancer.
abstract: Male breast cancer (MBC) is a rare disease and its biology is poorly understood. Deregulated Hippo pathway promotes oncogenic functions in female breast cancer. We herein investigated the expression of the Hippo transducers TAZ/YAP and their target CTGF in MBC. Tissue microarrays containing samples from 255 MBC patients were immunostained for TAZ, YAP and CTGF. One hundred and twenty-nine patients were considered eligible. The Pearson's Chi-squared test of independence was used to test the association between categorical variables. The correlation between TAZ, YAP and CTGF was assessed with the Pearson's correlation coefficient. The Kaplan-Meier method and the log-rank test were used for estimating and comparing survival curves. Cox proportional regression models were built to identify variables impacting overall survival. Statistical tests were two-sided. Tumors were considered to harbor active TAZ/YAP-driven gene transcription when they co-expressed TAZ, or YAP, and CTGF. Patients whose tumors had the TAZ/CTGF and YAP/CTGF phenotypes experienced shorter overall survival compared with their negative counterparts (log rank p = 0.036 for both). TAZ/CTGF and YAP/CTGF tumors were associated with decreased survival in patients with invasive ductal carcinomas, G3 tumors, hormone receptor-positive tumors, and tumors with elevated Ki-67. Multivariate analyses confirmed that the TAZ/CTGF and YAP/CTGF phenotypes are independent predictors of survival (HR 2.03, 95% CI: 1.06-3.90, p = 0.033; and HR 2.00, 95% CI: 1.04-3.84, p = 0.037 respectively). Comparable results were obtained when excluding uncommon histotypes (TAZ/CTGF: HR 2.34, 95% CI: 1.16-4.73, p = 0.018. YAP/CTGF. HR 2.36, 95% CI: 1.17-4.77, p = 0.017). Overall, the TAZ/YAP-driven oncogenic program may be active in MBC, conferring poorer survival.
authors.affiliation: Department of Pathology, "Regina Elena" National Cancer Institute, Rome, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Di Benedetto
authors.affiliation: Department of 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: Department of Pathology, "Regina Elena" National Cancer Institute, Rome, Italy.
authors.forename: Cristiana
authors.initials: C
authors.lastname: Ercolani
authors.affiliation: Division of Medical Oncology B, "Regina Elena" National Cancer Institute, Rome, Italy.
authors.forename: Luigi
authors.initials: L
authors.lastname: Di Lauro
authors.affiliation: Division of Medical Oncology B, "Regina Elena" National Cancer Institute, Rome, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Pizzuti
authors.affiliation: Division of Medical Oncology B, "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: Biostatistics-Scientific Direction, "Regina Elena" National Cancer Institute, Rome, Italy.
authors.forename: Isabella
authors.initials: I
authors.lastname: Sperduti
authors.affiliation: Department of Pathology, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK.
authors.forename: Abeer M
authors.initials: AM
authors.lastname: Shaaban
authors.affiliation: Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, UK.
authors.forename: Sreekumar
authors.initials: S
authors.lastname: Sundara-Rajan
authors.affiliation: Division of Medical Oncology B, "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, University of Leeds, Leeds, UK.
authors.forename: Valerie
authors.initials: V
authors.lastname: Speirs
authors.affiliation: Scientific Direction, "Regina Elena" National Cancer Institute, Rome, Italy.
authors.forename: Ruggero
authors.initials: R
authors.lastname: De Maria
authors.affiliation: Division of Medical Oncology B, "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: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018567:Breast Neoplasms, Male / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D063646:Carcinogenesis / Q000235:genetics; D018270:Carcinoma, Ductal, Breast / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D055513:Connective Tissue Growth Factor / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D000090683:Hippo Signaling Pathway; D006801:Humans; D007150:Immunohistochemistry; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D053208:Kaplan-Meier Estimate; D019394:Ki-67 Antigen / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D060787:Neoplasm Grading; D010641:Phenotype; D010750:Phosphoproteins / Q000378:metabolism*; D016016:Proportional Hazards Models; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D035583:Rare Diseases / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D011987:Receptors, Steroid / Q000378:metabolism; D012189:Retrospective Studies; D015398:Signal Transduction / Q000235:genetics; D046888:Tissue Array Analysis; D015534:Trans-Activators; D014157:Transcription Factors; D000091364:Transcriptional Coactivator with PDZ-Binding Motif Proteins; D000091102:YAP-Signaling Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C526317:CCN2 protein, human; D047908:Intracellular Signaling Peptides and Proteins; D019394:Ki-67 Antigen; D010750:Phosphoproteins; D011987:Receptors, Steroid; D015534:Trans-Activators; D014157:Transcription Factors; D000091364:Transcriptional Coactivator with PDZ-Binding Motif Proteins; C551991:WWTR1 protein, human; D000091102:YAP-Signaling Proteins; C088374:YAP1 protein, human; D055513:Connective Tissue Growth Factor; D017346:Protein Serine-Threonine Kinases
keywords: Hippo pathway; Hippo transducers; TAZ; YAP; male breast cancer