Association between AXL, Hippo Transducers, and Survival Outcomes in Male Breast Cancer

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

Research output: Contribution to journalArticle

5 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)2246-2252
Number of pages7
JournalJournal of Cellular Physiology
Volume232
Issue number8
Early online date3 Mar 2017
DOIs
Publication statusPublished - Aug 2017

Fingerprint

Male Breast Neoplasms
Transducers
Survival
Biomarkers
Transcription
Microarrays
Tumors
Chemical activation
Association reactions
Tissue
Rare Diseases
Proportional Hazards Models
Neoplasms
Multivariate Analysis
Phenotype

Keywords

  • Adaptor Proteins, Signal Transducing
  • Aged
  • Biomarkers, Tumor
  • Breast Neoplasms, Male
  • Chi-Square Distribution
  • Connective Tissue Growth Factor
  • Humans
  • Immunohistochemistry
  • Kaplan-Meier Estimate
  • Male
  • Middle Aged
  • Multivariate Analysis
  • Phosphoproteins
  • Predictive Value of Tests
  • Prognosis
  • Proportional Hazards Models
  • Proto-Oncogene Proteins
  • Receptor Protein-Tyrosine Kinases
  • Retrospective Studies
  • Risk Factors
  • Signal Transduction
  • Time Factors
  • Tissue Array Analysis
  • Transcription Factors
  • Journal Article

Cite this

Di Benedetto, A., Mottolese, M., Sperati, F., Ercolani, C., Di Lauro, L., Pizzuti, L., ... Maugeri-Saccà, M. (2017). Association between AXL, Hippo Transducers, and Survival Outcomes in Male Breast Cancer. Journal of Cellular Physiology, 232(8), 2246-2252. https://doi.org/10.1002/jcp.25745

Association between AXL, Hippo Transducers, and Survival Outcomes in Male Breast Cancer. / Di Benedetto, Anna; Mottolese, Marcella; Sperati, Francesca; Ercolani, Cristiana; Di Lauro, Luigi; Pizzuti, Laura; Vici, Patrizia; Terrenato, Irene; Shaaban, Abeer M; Humphries, Matthew P; Sundara-Rajan, Sreekumar; Barba, Maddalena; Speirs, Valerie; De Maria, Ruggero; Maugeri-Saccà, Marcello.

In: Journal of Cellular Physiology, Vol. 232, No. 8, 08.2017, p. 2246-2252.

Research output: Contribution to journalArticle

Di Benedetto, A, Mottolese, M, Sperati, F, Ercolani, C, Di Lauro, L, Pizzuti, L, Vici, P, Terrenato, I, Shaaban, AM, Humphries, MP, Sundara-Rajan, S, Barba, M, Speirs, V, De Maria, R & Maugeri-Saccà, M 2017, 'Association between AXL, Hippo Transducers, and Survival Outcomes in Male Breast Cancer', Journal of Cellular Physiology, vol. 232, no. 8, pp. 2246-2252. https://doi.org/10.1002/jcp.25745
Di Benedetto A, Mottolese M, Sperati F, Ercolani C, Di Lauro L, Pizzuti L et al. Association between AXL, Hippo Transducers, and Survival Outcomes in Male Breast Cancer. Journal of Cellular Physiology. 2017 Aug;232(8):2246-2252. https://doi.org/10.1002/jcp.25745
Di Benedetto, Anna ; Mottolese, Marcella ; Sperati, Francesca ; Ercolani, Cristiana ; Di Lauro, Luigi ; Pizzuti, Laura ; Vici, Patrizia ; Terrenato, Irene ; Shaaban, Abeer M ; Humphries, Matthew P ; Sundara-Rajan, Sreekumar ; Barba, Maddalena ; Speirs, Valerie ; De Maria, Ruggero ; Maugeri-Saccà, Marcello. / Association between AXL, Hippo Transducers, and Survival Outcomes in Male Breast Cancer. In: Journal of Cellular Physiology. 2017 ; Vol. 232, No. 8. pp. 2246-2252.
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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. {\circledC} 2016 Wiley Periodicals, Inc.",
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author = "{Di Benedetto}, Anna and Marcella Mottolese and Francesca Sperati and Cristiana Ercolani and {Di Lauro}, Luigi and Laura Pizzuti and Patrizia Vici and Irene Terrenato and Shaaban, {Abeer M} and Humphries, {Matthew P} and Sreekumar Sundara-Rajan and Maddalena Barba and Valerie Speirs and {De Maria}, Ruggero and Marcello Maugeri-Sacc{\`a}",
note = "Funding Information: “Associazione Italiana per la Ricerca sul Cancro” (AIRC IG). Grant Number: N:13431, Breast Cancer Now (formerly Breast Cancer Campaign). Grant Number: 2007MayPR02, Yorkshire Cancer Research. Grant Number: L378",
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T1 - Association between AXL, Hippo Transducers, and Survival Outcomes 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 - Shaaban, Abeer M

AU - Humphries, Matthew P

AU - Sundara-Rajan, Sreekumar

AU - Barba, Maddalena

AU - Speirs, Valerie

AU - De Maria, Ruggero

AU - Maugeri-Saccà, Marcello

N1 - Funding Information: “Associazione Italiana per la Ricerca sul Cancro” (AIRC IG). Grant Number: N:13431, Breast Cancer Now (formerly Breast Cancer Campaign). Grant Number: 2007MayPR02, Yorkshire Cancer Research. Grant Number: L378

PY - 2017/8

Y1 - 2017/8

N2 - 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.

AB - 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.

KW - Adaptor Proteins, Signal Transducing

KW - Aged

KW - Biomarkers, Tumor

KW - Breast Neoplasms, Male

KW - Chi-Square Distribution

KW - Connective Tissue Growth Factor

KW - Humans

KW - Immunohistochemistry

KW - Kaplan-Meier Estimate

KW - Male

KW - Middle Aged

KW - Multivariate Analysis

KW - Phosphoproteins

KW - Predictive Value of Tests

KW - Prognosis

KW - Proportional Hazards Models

KW - Proto-Oncogene Proteins

KW - Receptor Protein-Tyrosine Kinases

KW - Retrospective Studies

KW - Risk Factors

KW - Signal Transduction

KW - Time Factors

KW - Tissue Array Analysis

KW - Transcription Factors

KW - Journal Article

UR - http://eprints.whiterose.ac.uk/109623/

U2 - 10.1002/jcp.25745

DO - 10.1002/jcp.25745

M3 - Article

C2 - 27987320

VL - 232

SP - 2246

EP - 2252

JO - Journal of Cellular Physiology

JF - Journal of Cellular Physiology

SN - 0021-9541

IS - 8

ER -