The Hippo transducers TAZ/YAP and their target CTGF in male breast cancer
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Anna Di Benedetto1,*, Marcella Mottolese1,*, Francesca Sperati2, Cristiana Ercolani1, Luigi Di Lauro3, Laura Pizzuti3, Patrizia Vici3, Irene Terrenato2, Isabella Sperduti2, Abeer M. Shaaban4, Sreekumar Sundara-Rajan5, Maddalena Barba3,6, Valerie Speirs5, Ruggero De Maria6,#, Marcello Maugeri-Saccà3,6,#
1Department of Pathology, “Regina Elena” National Cancer Institute, Rome, Italy
2Biostatistics-Scientific Direction, “Regina Elena” National Cancer Institute, Rome, Italy
3Division of Medical Oncology B, “Regina Elena” National Cancer Institute, Rome, Italy
4Department of Pathology, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK
5Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, UK
6Scientific Direction, “Regina Elena” National Cancer Institute, Rome, Italy
*These authors contributed equally to this work
#These authors have contributed equally and share senior authorship
Marcello Mauger-Saccà, email: firstname.lastname@example.org
Valerie Speirs, email: email@example.com
Keywords: male breast cancer, Hippo pathway, Hippo transducers, TAZ, YAP
Received: April 06, 2016 Accepted: May 10, 2016 Published: May 27, 2016
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.
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