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. © 2016 Wiley Periodicals, Inc.

• Authors: 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
• Journal: Journal of cellular physiology (J Cell Physiol) Vol. 232 Issue 8 Pg. 2246-2252 (Aug 2017) ISSN: 1097-4652 [Electronic] United States
• PMID: 27987320 (Publication Type: Journal Article)
• Copyright: © 2016 Wiley Periodicals, Inc.

Chemical References

• Adaptor Proteins, Signal Transducing
• Biomarkers, Tumor
• CCN2 protein, human
• Phosphoproteins
• Proto-Oncogene Proteins
• Transcription Factors
• YAP-Signaling Proteins
• YAP1 protein, human
• Connective Tissue Growth Factor
• Acyltransferases
• TAFAZZIN protein, human
• Receptor Protein-Tyrosine Kinases
• Axl Receptor Tyrosine Kinase
• AXL protein, human

Topics

• Acyltransferases
• Adaptor Proteins, Signal Transducing (analysis)
• Aged
• Biomarkers, Tumor (analysis)
• Breast Neoplasms, Male (chemistry, mortality, pathology)
• Chi-Square Distribution
• Connective Tissue Growth Factor (analysis)
• Humans
• Immunohistochemistry
• Kaplan-Meier Estimate
• Male
• Middle Aged
• Multivariate Analysis
• Phosphoproteins (analysis)
• Predictive Value of Tests
• Prognosis
• Proportional Hazards Models
• Proto-Oncogene Proteins (analysis)
• Receptor Protein-Tyrosine Kinases (analysis)
• Retrospective Studies
• Risk Factors
• Signal Transduction
• Time Factors
• Tissue Array Analysis
• Transcription Factors (analysis)
• YAP-Signaling Proteins
• Axl Receptor Tyrosine Kinase