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

Fingerprint

Male Breast Neoplasms
Transducers
Survival
Neoplasms
Phenotype
Ductal Carcinoma
Rare Diseases
Multivariate Analysis
Hormones
Breast Neoplasms
Genes

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

Cite this

Di Benedetto, A., Mottolese, M., Sperati, F., Ercolani, C., Di Lauro, L., Pizzuti, L., ... 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

The Hippo transducers TAZ/YAP and their target CTGF in male breast cancer. / Di Benedetto, Anna; Mottolese, Marcella; Sperati, Francesca; Ercolani, Cristiana; Di Lauro, Luigi; Pizzuti, Laura; Vici, Patrizia; Terrenato, Irene; Sperduti, Isabella; Shaaban, Abeer M; Sundara-Rajan, Sreekumar; Barba, Maddalena; Speirs, Valerie; De Maria, Ruggero; Maugeri-Saccà, Marcello.

In: Oncotarget, Vol. 7, No. 28, 12.07.2016, p. 43188-43198.

Research output: Contribution to journalArticle

Di Benedetto, A, Mottolese, M, Sperati, F, Ercolani, C, Di Lauro, L, Pizzuti, L, Vici, P, Terrenato, I, Sperduti, I, Shaaban, AM, 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, vol. 7, no. 28, pp. 43188-43198. https://doi.org/10.18632/oncotarget.9668
Di Benedetto A, Mottolese M, Sperati F, Ercolani C, Di Lauro L, Pizzuti L et al. The Hippo transducers TAZ/YAP and their target CTGF in male breast cancer. Oncotarget. 2016 Jul 12;7(28):43188-43198. https://doi.org/10.18632/oncotarget.9668
Di Benedetto, Anna ; Mottolese, Marcella ; Sperati, Francesca ; Ercolani, Cristiana ; Di Lauro, Luigi ; Pizzuti, Laura ; Vici, Patrizia ; Terrenato, Irene ; Sperduti, Isabella ; Shaaban, Abeer M ; Sundara-Rajan, Sreekumar ; Barba, Maddalena ; Speirs, Valerie ; De Maria, Ruggero ; Maugeri-Saccà, Marcello. / The Hippo transducers TAZ/YAP and their target CTGF in male breast cancer. In: Oncotarget. 2016 ; Vol. 7, No. 28. pp. 43188-43198.
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note = "This study was supported by the “Associazione Italiana per la Ricerca sul Cancro” (AIRC IG Grant N:13431 to RDM), and by Breast Cancer Now (formerly Breast Cancer Campaign; grant 2007MayPR02 to VS and AMS), which provided funding for the accrual and construction of the MBC TMAs described.",
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T1 - The Hippo transducers TAZ/YAP and their target CTGF in male breast cancer

AU - Di Benedetto, Anna

AU - Mottolese, Marcella

AU - Sperati, Francesca

AU - Ercolani, Cristiana

AU - Di Lauro, Luigi

AU - Pizzuti, Laura

AU - Vici, Patrizia

AU - Terrenato, Irene

AU - Sperduti, Isabella

AU - Shaaban, Abeer M

AU - Sundara-Rajan, Sreekumar

AU - Barba, Maddalena

AU - Speirs, Valerie

AU - De Maria, Ruggero

AU - Maugeri-Saccà, Marcello

N1 - This study was supported by the “Associazione Italiana per la Ricerca sul Cancro” (AIRC IG Grant N:13431 to RDM), and by Breast Cancer Now (formerly Breast Cancer Campaign; grant 2007MayPR02 to VS and AMS), which provided funding for the accrual and construction of the MBC TMAs described.

PY - 2016/7/12

Y1 - 2016/7/12

N2 - 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.

AB - 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.

KW - Adaptor Proteins, Signal Transducing

KW - Adult

KW - Aged

KW - Aged, 80 and over

KW - Breast Neoplasms, Male

KW - Carcinogenesis

KW - Carcinoma, Ductal, Breast

KW - Connective Tissue Growth Factor

KW - Gene Expression Regulation, Neoplastic

KW - Humans

KW - Immunohistochemistry

KW - Intracellular Signaling Peptides and Proteins

KW - Kaplan-Meier Estimate

KW - Ki-67 Antigen

KW - Male

KW - Middle Aged

KW - Neoplasm Grading

KW - Phenotype

KW - Phosphoproteins

KW - Proportional Hazards Models

KW - Protein-Serine-Threonine Kinases

KW - Rare Diseases

KW - Receptors, Steroid

KW - Retrospective Studies

KW - Signal Transduction

KW - Tissue Array Analysis

KW - Journal Article

U2 - 10.18632/oncotarget.9668

DO - 10.18632/oncotarget.9668

M3 - Article

VL - 7

SP - 43188

EP - 43198

JO - Oncotarget

JF - Oncotarget

SN - 1949-2553

IS - 28

ER -