Systems biology analysis reveals NFAT5 as a novel biomarker and master regulator of inflammatory breast cancer

Andrea Remo, Ines Simeone, Massimo Pancione, Pietro Parcesepe, Pascal Finetti, Luigi Cerulo, Halima Bensmail, Daniel Birnbaum, Steven J. Van Laere, Vittorio Colantuoni, Franco Bonetti, François Bertucci, Erminia Manfrin, Michele Ceccarelli

Research output: Contribution to journalArticle

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Abstract

Background: Inflammatory breast cancer (IBC) is the most rare and aggressive variant of breast cancer (BC); however, only a limited number of specific gene signatures with low generalization abilities are available and few reliable biomarkers are helpful to improve IBC classification into a molecularly distinct phenotype. We applied a network-based strategy to gain insight into master regulators (MRs) linked to IBC pathogenesis. Methods: In-silico modeling and Algorithm for the Reconstruction of Accurate Cellular Networks (ARACNe) on IBC/non-IBC (nIBC) gene expression data (n = 197) was employed to identify novel master regulators connected to the IBC phenotype. Pathway enrichment analysis was used to characterize predicted targets of candidate genes. The expression pattern of the most significant MRs was then evaluated by immunohistochemistry (IHC) in two independent cohorts of IBCs (n = 39) and nIBCs (n = 82) and normal breast tissues (n = 15) spotted on tissue microarrays. The staining pattern of non-neoplastic mammary epithelial cells was used as a normal control. Results: Using in-silico modeling of network-based strategy, we identified three top enriched MRs (NFAT5, CTNNB1 or β-catenin, and MGA) strongly linked to the IBC phenotype. By IHC assays, we found that IBC patients displayed a higher number of NFAT5-positive cases than nIBC (69.2% vs. 19.5%; p-value = 2.79 10<sup>-7</sup>). Accordingly, the majority of NFAT5-positive IBC samples revealed an aberrant nuclear expression in comparison with nIBC samples (70% vs. 12.5%; p-value = 0.000797). NFAT5 nuclear accumulation occurs regardless of WNT/β-catenin activated signaling in a substantial portion of IBCs, suggesting that NFAT5 pathway activation may have a relevant role in IBC pathogenesis. Accordingly, cytoplasmic NFAT5 and membranous β-catenin expression were preferentially linked to nIBC, accounting for the better prognosis of this phenotype. Conclusions: We provide evidence that NFAT-signaling pathway activation could help to identify aggressive forms of BC and potentially be a guide to assignment of phenotype-specific therapeutic agents. The NFAT5 transcription factor might be developed into routine clinical practice as a putative biomarker of IBC phenotype.

Original languageEnglish
Article number138
JournalJournal of Translational Medicine
Volume13
Issue number1
DOIs
Publication statusPublished - 1 May 2015

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Inflammatory Breast Neoplasms
Catenins
Systems Biology
Biomarkers
Genes
Chemical activation
Tissue
Phenotype
Microarrays
Gene expression
Assays
Transcription Factors
Breast Neoplasms
Computer Simulation
Breast
Immunohistochemistry
Neoplasm Genes
Epithelial Cells

Keywords

  • CTNNB1
  • Gene regulatory network
  • Inflammatory breast cancer
  • MGA
  • NFAT5
  • Systems biology

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Systems biology analysis reveals NFAT5 as a novel biomarker and master regulator of inflammatory breast cancer. / Remo, Andrea; Simeone, Ines; Pancione, Massimo; Parcesepe, Pietro; Finetti, Pascal; Cerulo, Luigi; Bensmail, Halima; Birnbaum, Daniel; Van Laere, Steven J.; Colantuoni, Vittorio; Bonetti, Franco; Bertucci, François; Manfrin, Erminia; Ceccarelli, Michele.

In: Journal of Translational Medicine, Vol. 13, No. 1, 138, 01.05.2015.

Research output: Contribution to journalArticle

Remo, A, Simeone, I, Pancione, M, Parcesepe, P, Finetti, P, Cerulo, L, Bensmail, H, Birnbaum, D, Van Laere, SJ, Colantuoni, V, Bonetti, F, Bertucci, F, Manfrin, E & Ceccarelli, M 2015, 'Systems biology analysis reveals NFAT5 as a novel biomarker and master regulator of inflammatory breast cancer', Journal of Translational Medicine, vol. 13, no. 1, 138. https://doi.org/10.1186/s12967-015-0492-2
Remo, Andrea ; Simeone, Ines ; Pancione, Massimo ; Parcesepe, Pietro ; Finetti, Pascal ; Cerulo, Luigi ; Bensmail, Halima ; Birnbaum, Daniel ; Van Laere, Steven J. ; Colantuoni, Vittorio ; Bonetti, Franco ; Bertucci, François ; Manfrin, Erminia ; Ceccarelli, Michele. / Systems biology analysis reveals NFAT5 as a novel biomarker and master regulator of inflammatory breast cancer. In: Journal of Translational Medicine. 2015 ; Vol. 13, No. 1.
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abstract = "Background: Inflammatory breast cancer (IBC) is the most rare and aggressive variant of breast cancer (BC); however, only a limited number of specific gene signatures with low generalization abilities are available and few reliable biomarkers are helpful to improve IBC classification into a molecularly distinct phenotype. We applied a network-based strategy to gain insight into master regulators (MRs) linked to IBC pathogenesis. Methods: In-silico modeling and Algorithm for the Reconstruction of Accurate Cellular Networks (ARACNe) on IBC/non-IBC (nIBC) gene expression data (n = 197) was employed to identify novel master regulators connected to the IBC phenotype. Pathway enrichment analysis was used to characterize predicted targets of candidate genes. The expression pattern of the most significant MRs was then evaluated by immunohistochemistry (IHC) in two independent cohorts of IBCs (n = 39) and nIBCs (n = 82) and normal breast tissues (n = 15) spotted on tissue microarrays. The staining pattern of non-neoplastic mammary epithelial cells was used as a normal control. Results: Using in-silico modeling of network-based strategy, we identified three top enriched MRs (NFAT5, CTNNB1 or β-catenin, and MGA) strongly linked to the IBC phenotype. By IHC assays, we found that IBC patients displayed a higher number of NFAT5-positive cases than nIBC (69.2{\%} vs. 19.5{\%}; p-value = 2.79 10-7). Accordingly, the majority of NFAT5-positive IBC samples revealed an aberrant nuclear expression in comparison with nIBC samples (70{\%} vs. 12.5{\%}; p-value = 0.000797). NFAT5 nuclear accumulation occurs regardless of WNT/β-catenin activated signaling in a substantial portion of IBCs, suggesting that NFAT5 pathway activation may have a relevant role in IBC pathogenesis. Accordingly, cytoplasmic NFAT5 and membranous β-catenin expression were preferentially linked to nIBC, accounting for the better prognosis of this phenotype. Conclusions: We provide evidence that NFAT-signaling pathway activation could help to identify aggressive forms of BC and potentially be a guide to assignment of phenotype-specific therapeutic agents. The NFAT5 transcription factor might be developed into routine clinical practice as a putative biomarker of IBC phenotype.",
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AU - Simeone, Ines

AU - Pancione, Massimo

AU - Parcesepe, Pietro

AU - Finetti, Pascal

AU - Cerulo, Luigi

AU - Bensmail, Halima

AU - Birnbaum, Daniel

AU - Van Laere, Steven J.

AU - Colantuoni, Vittorio

AU - Bonetti, Franco

AU - Bertucci, François

AU - Manfrin, Erminia

AU - Ceccarelli, Michele

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N2 - Background: Inflammatory breast cancer (IBC) is the most rare and aggressive variant of breast cancer (BC); however, only a limited number of specific gene signatures with low generalization abilities are available and few reliable biomarkers are helpful to improve IBC classification into a molecularly distinct phenotype. We applied a network-based strategy to gain insight into master regulators (MRs) linked to IBC pathogenesis. Methods: In-silico modeling and Algorithm for the Reconstruction of Accurate Cellular Networks (ARACNe) on IBC/non-IBC (nIBC) gene expression data (n = 197) was employed to identify novel master regulators connected to the IBC phenotype. Pathway enrichment analysis was used to characterize predicted targets of candidate genes. The expression pattern of the most significant MRs was then evaluated by immunohistochemistry (IHC) in two independent cohorts of IBCs (n = 39) and nIBCs (n = 82) and normal breast tissues (n = 15) spotted on tissue microarrays. The staining pattern of non-neoplastic mammary epithelial cells was used as a normal control. Results: Using in-silico modeling of network-based strategy, we identified three top enriched MRs (NFAT5, CTNNB1 or β-catenin, and MGA) strongly linked to the IBC phenotype. By IHC assays, we found that IBC patients displayed a higher number of NFAT5-positive cases than nIBC (69.2% vs. 19.5%; p-value = 2.79 10-7). Accordingly, the majority of NFAT5-positive IBC samples revealed an aberrant nuclear expression in comparison with nIBC samples (70% vs. 12.5%; p-value = 0.000797). NFAT5 nuclear accumulation occurs regardless of WNT/β-catenin activated signaling in a substantial portion of IBCs, suggesting that NFAT5 pathway activation may have a relevant role in IBC pathogenesis. Accordingly, cytoplasmic NFAT5 and membranous β-catenin expression were preferentially linked to nIBC, accounting for the better prognosis of this phenotype. Conclusions: We provide evidence that NFAT-signaling pathway activation could help to identify aggressive forms of BC and potentially be a guide to assignment of phenotype-specific therapeutic agents. The NFAT5 transcription factor might be developed into routine clinical practice as a putative biomarker of IBC phenotype.

AB - Background: Inflammatory breast cancer (IBC) is the most rare and aggressive variant of breast cancer (BC); however, only a limited number of specific gene signatures with low generalization abilities are available and few reliable biomarkers are helpful to improve IBC classification into a molecularly distinct phenotype. We applied a network-based strategy to gain insight into master regulators (MRs) linked to IBC pathogenesis. Methods: In-silico modeling and Algorithm for the Reconstruction of Accurate Cellular Networks (ARACNe) on IBC/non-IBC (nIBC) gene expression data (n = 197) was employed to identify novel master regulators connected to the IBC phenotype. Pathway enrichment analysis was used to characterize predicted targets of candidate genes. The expression pattern of the most significant MRs was then evaluated by immunohistochemistry (IHC) in two independent cohorts of IBCs (n = 39) and nIBCs (n = 82) and normal breast tissues (n = 15) spotted on tissue microarrays. The staining pattern of non-neoplastic mammary epithelial cells was used as a normal control. Results: Using in-silico modeling of network-based strategy, we identified three top enriched MRs (NFAT5, CTNNB1 or β-catenin, and MGA) strongly linked to the IBC phenotype. By IHC assays, we found that IBC patients displayed a higher number of NFAT5-positive cases than nIBC (69.2% vs. 19.5%; p-value = 2.79 10-7). Accordingly, the majority of NFAT5-positive IBC samples revealed an aberrant nuclear expression in comparison with nIBC samples (70% vs. 12.5%; p-value = 0.000797). NFAT5 nuclear accumulation occurs regardless of WNT/β-catenin activated signaling in a substantial portion of IBCs, suggesting that NFAT5 pathway activation may have a relevant role in IBC pathogenesis. Accordingly, cytoplasmic NFAT5 and membranous β-catenin expression were preferentially linked to nIBC, accounting for the better prognosis of this phenotype. Conclusions: We provide evidence that NFAT-signaling pathway activation could help to identify aggressive forms of BC and potentially be a guide to assignment of phenotype-specific therapeutic agents. The NFAT5 transcription factor might be developed into routine clinical practice as a putative biomarker of IBC phenotype.

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