The Hippo transducers TAZ/YAP and their target CTGF in male breast cancer

Anna Di Benedetto, Marcella Mottolese, Francesca Sperati, Cristiana Ercolani, Luigi Di Lauro, Laura Pizzuti, Patrizia Vici, Irene Terrenato, Isabella Sperduti, Abeer M Shaaban, Sreekumar Sundara-Rajan, Maddalena Barba, Valerie Speirs, Ruggero De Maria, Marcello Maugeri-Saccà

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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.

Original languageEnglish
Pages (from-to)43188-43198
Number of pages11
JournalOncotarget
Volume7
Issue number28
DOIs
Publication statusPublished - 12 Jul 2016

Keywords

  • Adaptor Proteins, Signal Transducing
  • Adult
  • Aged
  • Aged, 80 and over
  • Breast Neoplasms, Male
  • Carcinogenesis
  • Carcinoma, Ductal, Breast
  • Connective Tissue Growth Factor
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Immunohistochemistry
  • Intracellular Signaling Peptides and Proteins
  • Kaplan-Meier Estimate
  • Ki-67 Antigen
  • Male
  • Middle Aged
  • Neoplasm Grading
  • Phenotype
  • Phosphoproteins
  • Proportional Hazards Models
  • Protein-Serine-Threonine Kinases
  • Rare Diseases
  • Receptors, Steroid
  • Retrospective Studies
  • Signal Transduction
  • Tissue Array Analysis
  • Journal Article

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    Di Benedetto, A., Mottolese, M., Sperati, F., Ercolani, C., Di Lauro, L., Pizzuti, L., Vici, P., Terrenato, I., Sperduti, I., Shaaban, A. M., Sundara-Rajan, S., Barba, M., Speirs, V., De Maria, R., & Maugeri-Saccà, M. (2016). The Hippo transducers TAZ/YAP and their target CTGF in male breast cancer. Oncotarget, 7(28), 43188-43198. https://doi.org/10.18632/oncotarget.9668