Systems biology analysis reveals NFAT5 as a novel biomarker and master regulator of inflammatory breast cancer
<h3>Background</h3><p dir="ltr">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 helpf...
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| مؤلفون آخرون: | , , , , , , , , , , , , |
| منشور في: |
2015
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| _version_ | 1864513506048475136 |
|---|---|
| author | Andrea Remo (447375) |
| author2 | Ines Simeone (15239242) Massimo Pancione (235937) Pietro Parcesepe (3439901) Pascal Finetti (65359) Luigi Cerulo (447376) Halima Bensmail (10400) Daniel Birnbaum (63368) Steven J Van Laere (19568752) Vittorio Colantuoni (235950) Franco Bonetti (3580025) François Bertucci (93540) Erminia Manfrin (447377) Michele Ceccarelli (184154) |
| author2_role | author author author author author author author author author author author author author |
| author_facet | Andrea Remo (447375) Ines Simeone (15239242) Massimo Pancione (235937) Pietro Parcesepe (3439901) Pascal Finetti (65359) Luigi Cerulo (447376) Halima Bensmail (10400) Daniel Birnbaum (63368) Steven J Van Laere (19568752) Vittorio Colantuoni (235950) Franco Bonetti (3580025) François Bertucci (93540) Erminia Manfrin (447377) Michele Ceccarelli (184154) |
| author_role | author |
| dc.creator.none.fl_str_mv | Andrea Remo (447375) Ines Simeone (15239242) Massimo Pancione (235937) Pietro Parcesepe (3439901) Pascal Finetti (65359) Luigi Cerulo (447376) Halima Bensmail (10400) Daniel Birnbaum (63368) Steven J Van Laere (19568752) Vittorio Colantuoni (235950) Franco Bonetti (3580025) François Bertucci (93540) Erminia Manfrin (447377) Michele Ceccarelli (184154) |
| dc.date.none.fl_str_mv | 2015-05-01T00:00:00Z |
| dc.identifier.none.fl_str_mv | 10.1186/s12967-015-0492-2 |
| dc.relation.none.fl_str_mv | https://figshare.com/articles/journal_contribution/Systems_biology_analysis_reveals_NFAT5_as_a_novel_biomarker_and_master_regulator_of_inflammatory_breast_cancer/26974774 |
| dc.rights.none.fl_str_mv | CC BY 4.0 info:eu-repo/semantics/openAccess |
| dc.subject.none.fl_str_mv | Biological sciences Biochemistry and cell biology Bioinformatics and computational biology Genetics Biomedical and clinical sciences Clinical sciences Oncology and carcinogenesis Inflammatory breast cancer Gene regulatory network Systems biology NFAT5 MGA CTNNB1 |
| dc.title.none.fl_str_mv | Systems biology analysis reveals NFAT5 as a novel biomarker and master regulator of inflammatory breast cancer |
| dc.type.none.fl_str_mv | Text Journal contribution info:eu-repo/semantics/publishedVersion text contribution to journal |
| description | <h3>Background</h3><p dir="ltr">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. </p><h3>Methods</h3><p dir="ltr">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. </p><h3>Results</h3><p dir="ltr">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. </p><h3>Conclusions</h3><p dir="ltr">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.</p><h2>Other Information</h2><p dir="ltr">Published in: Journal of Translational Medicine<br>License: <a href="http://creativecommons.org/licenses/by/4.0" target="_blank">http://creativecommons.org/licenses/by/4.0</a><br>See article on publisher's website: <a href="https://dx.doi.org/10.1186/s12967-015-0492-2" target="_blank">https://dx.doi.org/10.1186/s12967-015-0492-2</a></p> |
| eu_rights_str_mv | openAccess |
| id | Manara2_02d4fcc530ea9f1e51cffbcee8250398 |
| identifier_str_mv | 10.1186/s12967-015-0492-2 |
| network_acronym_str | Manara2 |
| network_name_str | Manara2 |
| oai_identifier_str | oai:figshare.com:article/26974774 |
| publishDate | 2015 |
| repository.mail.fl_str_mv | |
| repository.name.fl_str_mv | |
| repository_id_str | |
| rights_invalid_str_mv | CC BY 4.0 |
| spelling | Systems biology analysis reveals NFAT5 as a novel biomarker and master regulator of inflammatory breast cancerAndrea Remo (447375)Ines Simeone (15239242)Massimo Pancione (235937)Pietro Parcesepe (3439901)Pascal Finetti (65359)Luigi Cerulo (447376)Halima Bensmail (10400)Daniel Birnbaum (63368)Steven J Van Laere (19568752)Vittorio Colantuoni (235950)Franco Bonetti (3580025)François Bertucci (93540)Erminia Manfrin (447377)Michele Ceccarelli (184154)Biological sciencesBiochemistry and cell biologyBioinformatics and computational biologyGeneticsBiomedical and clinical sciencesClinical sciencesOncology and carcinogenesisInflammatory breast cancerGene regulatory networkSystems biologyNFAT5MGACTNNB1<h3>Background</h3><p dir="ltr">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. </p><h3>Methods</h3><p dir="ltr">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. </p><h3>Results</h3><p dir="ltr">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. </p><h3>Conclusions</h3><p dir="ltr">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.</p><h2>Other Information</h2><p dir="ltr">Published in: Journal of Translational Medicine<br>License: <a href="http://creativecommons.org/licenses/by/4.0" target="_blank">http://creativecommons.org/licenses/by/4.0</a><br>See article on publisher's website: <a href="https://dx.doi.org/10.1186/s12967-015-0492-2" target="_blank">https://dx.doi.org/10.1186/s12967-015-0492-2</a></p>2015-05-01T00:00:00ZTextJournal contributioninfo:eu-repo/semantics/publishedVersiontextcontribution to journal10.1186/s12967-015-0492-2https://figshare.com/articles/journal_contribution/Systems_biology_analysis_reveals_NFAT5_as_a_novel_biomarker_and_master_regulator_of_inflammatory_breast_cancer/26974774CC BY 4.0info:eu-repo/semantics/openAccessoai:figshare.com:article/269747742015-05-01T00:00:00Z |
| spellingShingle | Systems biology analysis reveals NFAT5 as a novel biomarker and master regulator of inflammatory breast cancer Andrea Remo (447375) Biological sciences Biochemistry and cell biology Bioinformatics and computational biology Genetics Biomedical and clinical sciences Clinical sciences Oncology and carcinogenesis Inflammatory breast cancer Gene regulatory network Systems biology NFAT5 MGA CTNNB1 |
| status_str | publishedVersion |
| title | Systems biology analysis reveals NFAT5 as a novel biomarker and master regulator of inflammatory breast cancer |
| title_full | Systems biology analysis reveals NFAT5 as a novel biomarker and master regulator of inflammatory breast cancer |
| title_fullStr | Systems biology analysis reveals NFAT5 as a novel biomarker and master regulator of inflammatory breast cancer |
| title_full_unstemmed | Systems biology analysis reveals NFAT5 as a novel biomarker and master regulator of inflammatory breast cancer |
| title_short | Systems biology analysis reveals NFAT5 as a novel biomarker and master regulator of inflammatory breast cancer |
| title_sort | Systems biology analysis reveals NFAT5 as a novel biomarker and master regulator of inflammatory breast cancer |
| topic | Biological sciences Biochemistry and cell biology Bioinformatics and computational biology Genetics Biomedical and clinical sciences Clinical sciences Oncology and carcinogenesis Inflammatory breast cancer Gene regulatory network Systems biology NFAT5 MGA CTNNB1 |