Neoplastic and Stromal Cells Contribute to an Extracellular Matrix Gene Expression Profile Defining a Breast Cancer Subtype Likely to Progress
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{"title"=>"Neoplastic and Stromal Cells Contribute to an Extracellular Matrix Gene Expression Profile Defining a Breast Cancer Subtype Likely to Progress", "type"=>"journal", "authors"=>[{"first_name"=>"Tiziana", "last_name"=>"Triulzi", "scopus_author_id"=>"23490657500"}, {"first_name"=>"Patrizia", "last_name"=>"Casalini", "scopus_author_id"=>"6701455901"}, {"first_name"=>"Marco", "last_name"=>"Sandri", "scopus_author_id"=>"36492255700"}, {"first_name"=>"Manuela", "last_name"=>"Ratti", "scopus_author_id"=>"55603269500"}, {"first_name"=>"Maria L.", "last_name"=>"Carcangiu", "scopus_author_id"=>"7005769488"}, {"first_name"=>"Mario P.", "last_name"=>"Colombo", "scopus_author_id"=>"7203013920"}, {"first_name"=>"Andrea", "last_name"=>"Balsari", "scopus_author_id"=>"7006375879"}, {"first_name"=>"Sylvie", "last_name"=>"Ménard", "scopus_author_id"=>"7101970914"}, {"first_name"=>"Rosaria", "last_name"=>"Orlandi", "scopus_author_id"=>"7007175632"}, {"first_name"=>"Elda", "last_name"=>"Tagliabue", "scopus_author_id"=>"7004273537"}], "year"=>2013, "source"=>"PLoS ONE", "identifiers"=>{"sgr"=>"84874165459", "doi"=>"10.1371/journal.pone.0056761", "pui"=>"368381794", "pmid"=>"23441215", "scopus"=>"2-s2.0-84874165459", "issn"=>"19326203", "isbn"=>"1932-6203 (Electronic)\\r1932-6203 (Linking)"}, "id"=>"88fd97e0-90fa-38e0-adb1-0946e1f890fc", "abstract"=>"We recently showed that differential expression of extracellular matrix (ECM) genes delineates four subgroups of breast carcinomas (ECM1, -2, -3- and -4) with different clinical outcome. To further investigate the characteristics of ECM signature and its impact on tumor progression, we conducted unsupervised clustering analyses in 6 additional independent datasets of invasive breast tumors from different platforms for a total of 643 samples. Use of four different clustering algorithms identified ECM3 tumors as an independent group in all datasets tested. ECM3 showed a homogeneous gene pattern, consisting of 58 genes encoding 43 structural ECM proteins. From 26 to 41% of the cases were ECM3-enriched, and analysis of datasets relevant to gene expression in neoplastic or corresponding stromal cells showed that both stromal and breast carcinoma cells can coordinately express ECM3 genes. In in vitro experiments, β-estradiol induced ECM3 gene production in ER-positive breast carcinoma cell lines, whereas TGFβ induced upregulation of the genes leading to ECM3 gene classification, especially in ER-negative breast carcinoma cells and in fibroblasts. Multivariate analysis of distant metastasis-free survival in untreated breast tumor patients revealed a significant interaction between ECM3 and histological grade (p = 0.001). Cox models, estimated separately in grade I-II and grade III tumors, indicated a highly significant association between ECM3 and worse survival probability only in grade III tumors (HR = 3.0, 95% CI = 1.3-7.0, p = 0.0098). Gene Set Enrichment analysis of ECM3 compared to non-ECM3 tumors revealed significant enrichment of epithelial-mesenchymal transition (EMT) genes in both grade I-II and grade III subsets of ECM3 tumors. Thus, ECM3 is a robust cluster that identifies breast carcinomas with EMT features but with accelerated metastatic potential only in the undifferentiated (grade III) phenotype. These findings support the key relevance of neoplastic and stroma interaction in breast cancer progression.", "link"=>"http://www.mendeley.com/research/neoplastic-stromal-cells-contribute-extracellular-matrix-gene-expression-profile-defining-breast-can", "reader_count"=>34, "reader_count_by_academic_status"=>{"Professor > Associate Professor"=>2, "Researcher"=>11, "Student > Ph. D. Student"=>7, "Student > Postgraduate"=>2, "Student > Master"=>7, "Student > Bachelor"=>2, "Lecturer > Senior Lecturer"=>2, "Professor"=>1}, "reader_count_by_user_role"=>{"Professor > Associate Professor"=>2, "Researcher"=>11, "Student > Ph. D. Student"=>7, "Student > Postgraduate"=>2, "Student > Master"=>7, "Student > Bachelor"=>2, "Lecturer > Senior Lecturer"=>2, "Professor"=>1}, "reader_count_by_subject_area"=>{"Unspecified"=>2, "Engineering"=>1, "Biochemistry, Genetics and Molecular Biology"=>5, "Mathematics"=>1, "Medicine and Dentistry"=>3, "Agricultural and Biological Sciences"=>18, "Arts and Humanities"=>1, "Physics and Astronomy"=>1, "Chemistry"=>1, "Computer Science"=>1}, "reader_count_by_subdiscipline"=>{"Engineering"=>{"Engineering"=>1}, "Medicine and Dentistry"=>{"Medicine and Dentistry"=>3}, "Chemistry"=>{"Chemistry"=>1}, "Physics and Astronomy"=>{"Physics and Astronomy"=>1}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>18}, "Computer Science"=>{"Computer Science"=>1}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>5}, "Mathematics"=>{"Mathematics"=>1}, "Unspecified"=>{"Unspecified"=>2}, "Arts and Humanities"=>{"Arts and Humanities"=>1}}, "reader_count_by_country"=>{"Germany"=>1}, "group_count"=>4}

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/487328"], "description"=>"<p>Heatmap shows the normalized enrichment scores (NES) of gene sets significantly enriched at p<0.05 and FDR<25% in ECM3 grade III (A) and grade I–II (B) tumors of Desmedt <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0056761#pone.0056761-Desmedt1\" target=\"_blank\">[19]</a> and Chin <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0056761#pone.0056761-Chin1\" target=\"_blank\">[16]</a> datasets.</p>", "links"=>[], "tags"=>["characteristics", "carcinomas", "ecm", "classification", "enrichment"], "article_id"=>157837, "categories"=>["Biological Sciences", "Information And Computing Sciences", "Mathematics", "Cancer", "Molecular Biology", "Cell Biology"], "users"=>["Tiziana Triulzi", "Patrizia Casalini", "Marco Sandri", "Manuela Ratti", "Maria L. Carcangiu", "Mario P. Colombo", "Andrea Balsari", "Sylvie Menard", "Rosaria Orlandi", "Elda Tagliabue"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0056761.g005", "stats"=>{"downloads"=>0, "page_views"=>1, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Molecular_characteristics_of_breast_carcinomas_according_to_ECM_and_grade_classification_by_Gene_Set_Enrichment_Analysis_GSEA_/157837", "title"=>"Molecular characteristics of breast carcinomas according to ECM and grade classification by Gene Set Enrichment Analysis (GSEA).", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-02-18 02:10:37"}
  • {"files"=>["https://ndownloader.figshare.com/files/1004628"], "description"=>"*<p>Evaluated by Fisher exact test.</p>", "links"=>[], "tags"=>["clinico-pathological", "patients", "ecm3"], "article_id"=>665246, "categories"=>["Biological Sciences", "Information And Computing Sciences", "Mathematics", "Cancer", "Molecular Biology", "Cell Biology"], "users"=>["Tiziana Triulzi", "Patrizia Casalini", "Marco Sandri", "Manuela Ratti", "Maria L. Carcangiu", "Mario P. Colombo", "Andrea Balsari", "Sylvie Menard", "Rosaria Orlandi", "Elda Tagliabue"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0056761.t001", "stats"=>{"downloads"=>1, "page_views"=>3, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Frequency_of_clinico_pathological_characteristic_in_patients_according_to_ECM3_classification_/665246", "title"=>"Frequency of clinico-pathological characteristic in patients according to ECM3 classification.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2013-02-18 01:27:26"}
  • {"files"=>["https://ndownloader.figshare.com/files/1004649"], "description"=>"*<p>CI = confidence interval.</p>", "links"=>[], "tags"=>["proportional", "hazards", "metastasis-free", "untreated"], "article_id"=>665269, "categories"=>["Biological Sciences", "Information And Computing Sciences", "Mathematics", "Cancer", "Molecular Biology", "Cell Biology"], "users"=>["Tiziana Triulzi", "Patrizia Casalini", "Marco Sandri", "Manuela Ratti", "Maria L. Carcangiu", "Mario P. Colombo", "Andrea Balsari", "Sylvie Menard", "Rosaria Orlandi", "Elda Tagliabue"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0056761.t002", "stats"=>{"downloads"=>0, "page_views"=>6, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Multivariate_proportional_hazards_analysis_of_metastasis_free_survival_in_untreated_patients_/665269", "title"=>"Multivariate proportional hazards analysis of metastasis-free survival in untreated patients.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2013-02-18 01:27:49"}
  • {"files"=>["https://ndownloader.figshare.com/files/487023"], "description"=>"<p>(A) qPCR analysis of ECM3 score derived from the average expression levels of <i>COL1A1</i>, <i>COL5A2</i>, <i>SPARC</i> and <i>LAMA4</i> genes on FFPE specimens of 24 breast tumors of the ITA cohort <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0056761#pone.0056761-Bergamaschi1\" target=\"_blank\">[13]</a> classified as ECM3 or non-ECM3 by unsupervised clustering. ** p<0.01 in unpaired t-test. (B) Receiver-operator characteristics (ROC) curve for expression of ECM3 genes in the ECM3 tumor subgroup.</p>", "links"=>[], "tags"=>["classification", "carcinomas"], "article_id"=>157539, "categories"=>["Biological Sciences", "Information And Computing Sciences", "Mathematics", "Cancer", "Molecular Biology", "Cell Biology"], "users"=>["Tiziana Triulzi", "Patrizia Casalini", "Marco Sandri", "Manuela Ratti", "Maria L. Carcangiu", "Mario P. Colombo", "Andrea Balsari", "Sylvie Menard", "Rosaria Orlandi", "Elda Tagliabue"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0056761.g002", "stats"=>{"downloads"=>0, "page_views"=>2, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_ECM3_classification_of_breast_carcinomas_by_qRT_PCR_/157539", "title"=>"ECM3 classification of breast carcinomas by qRT-PCR.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-02-18 02:05:39"}
  • {"files"=>["https://ndownloader.figshare.com/files/487115"], "description"=>"<p>(A) Representative immunohistochemical staining for Collagen VI and SPARC in ECM3 and non-ECM3 breast tumors. Magnification: ×400. (B,C) Fold-increase in ECM3 score expression as assessed by qRT-PCR after treatment with TGFβ (B) and 17β-estradiol (C) in breast carcinoma and fibroblast cell lines. Dotted line indicates average ECM3 expression in untreated cell lines. *p<0.05 in unpaired t-test vs untreated cells.</p>", "links"=>[], "tags"=>["molecular biology", "Computational biology", "cell biology", "oncology", "computer science", "mathematics"], "article_id"=>157625, "categories"=>["Biological Sciences", "Information And Computing Sciences", "Mathematics", "Cancer", "Molecular Biology", "Cell Biology"], "users"=>["Tiziana Triulzi", "Patrizia Casalini", "Marco Sandri", "Manuela Ratti", "Maria L. Carcangiu", "Mario P. Colombo", "Andrea Balsari", "Sylvie Menard", "Rosaria Orlandi", "Elda Tagliabue"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0056761.g003", "stats"=>{"downloads"=>2, "page_views"=>9, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_ECM3_gene_expression_in_tumor_cells_/157625", "title"=>"ECM3 gene expression in tumor cells.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-02-18 02:07:05"}
  • {"files"=>["https://ndownloader.figshare.com/files/486934"], "description"=>"<p>(A) Expression profile of LAS biclustering in breast tumors from the Van't Veer dataset <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0056761#pone.0056761-VanTVeer1\" target=\"_blank\">[15]</a>. (B) Frequency distribution of most influential ECM3 genes in 6 datasets (<a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0056761#pone.0056761-VanTVeer1\" target=\"_blank\">[15]</a>–<a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0056761#pone.0056761-Sotiriou1\" target=\"_blank\">[20]</a>), tumor clustering and gene importance estimation.</p>", "links"=>[], "tags"=>["molecular biology", "Computational biology", "cell biology", "oncology", "computer science", "mathematics"], "article_id"=>157445, "categories"=>["Biological Sciences", "Information And Computing Sciences", "Mathematics", "Cancer", "Molecular Biology", "Cell Biology"], "users"=>["Tiziana Triulzi", "Patrizia Casalini", "Marco Sandri", "Manuela Ratti", "Maria L. Carcangiu", "Mario P. Colombo", "Andrea Balsari", "Sylvie Menard", "Rosaria Orlandi", "Elda Tagliabue"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0056761.g001", "stats"=>{"downloads"=>0, "page_views"=>7, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_ECM3_gene_pattern_in_breast_carcinomas_/157445", "title"=>"ECM3 gene pattern in breast carcinomas.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-02-18 02:04:05"}
  • {"files"=>["https://ndownloader.figshare.com/files/486736", "https://ndownloader.figshare.com/files/486738", "https://ndownloader.figshare.com/files/486742", "https://ndownloader.figshare.com/files/486744", "https://ndownloader.figshare.com/files/486748", "https://ndownloader.figshare.com/files/486750", "https://ndownloader.figshare.com/files/486752", "https://ndownloader.figshare.com/files/486753", "https://ndownloader.figshare.com/files/486754", "https://ndownloader.figshare.com/files/486756", "https://ndownloader.figshare.com/files/486759", "https://ndownloader.figshare.com/files/486763", "https://ndownloader.figshare.com/files/486765"], "description"=>"<div><p>We recently showed that differential expression of extracellular matrix (ECM) genes delineates four subgroups of breast carcinomas (ECM1, -2, -3- and -4) with different clinical outcome. To further investigate the characteristics of ECM signature and its impact on tumor progression, we conducted unsupervised clustering analyses in 6 additional independent datasets of invasive breast tumors from different platforms for a total of 643 samples. Use of four different clustering algorithms identified ECM3 tumors as an independent group in all datasets tested. ECM3 showed a homogeneous gene pattern, consisting of 58 genes encoding 43 structural ECM proteins. From 26 to 41% of the cases were ECM3-enriched, and analysis of datasets relevant to gene expression in neoplastic or corresponding stromal cells showed that both stromal and breast carcinoma cells can coordinately express ECM3 genes. In <i>in vitro</i> experiments, β-estradiol induced ECM3 gene production in ER-positive breast carcinoma cell lines, whereas TGFβ induced upregulation of the genes leading to ECM3 gene classification, especially in ER-negative breast carcinoma cells and in fibroblasts. Multivariate analysis of distant metastasis-free survival in untreated breast tumor patients revealed a significant interaction between ECM3 and histological grade (p = 0.001). Cox models, estimated separately in grade I–II and grade III tumors, indicated a highly significant association between ECM3 and worse survival probability only in grade III tumors (HR = 3.0, 95% CI = 1.3–7.0, p = 0.0098). Gene Set Enrichment analysis of ECM3 compared to non-ECM3 tumors revealed significant enrichment of epithelial-mesenchymal transition (EMT) genes in both grade I–II and grade III subsets of ECM3 tumors. Thus, ECM3 is a robust cluster that identifies breast carcinomas with EMT features but with accelerated metastatic potential only in the undifferentiated (grade III) phenotype. These findings support the key relevance of neoplastic and stroma interaction in breast cancer progression.</p> </div>", "links"=>[], "tags"=>["neoplastic", "stromal", "cells", "extracellular", "matrix", "cancer", "subtype", "progress"], "article_id"=>157316, "categories"=>["Biological Sciences", "Information And Computing Sciences", "Mathematics", "Cancer", "Molecular Biology", "Cell Biology"], "users"=>["Tiziana Triulzi", "Patrizia Casalini", "Marco Sandri", "Manuela Ratti", "Maria L. Carcangiu", "Mario P. Colombo", "Andrea Balsari", "Sylvie Menard", "Rosaria Orlandi", "Elda Tagliabue"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0056761.s001", "https://dx.doi.org/10.1371/journal.pone.0056761.s002", "https://dx.doi.org/10.1371/journal.pone.0056761.s003", "https://dx.doi.org/10.1371/journal.pone.0056761.s004", "https://dx.doi.org/10.1371/journal.pone.0056761.s005", "https://dx.doi.org/10.1371/journal.pone.0056761.s006", "https://dx.doi.org/10.1371/journal.pone.0056761.s007", "https://dx.doi.org/10.1371/journal.pone.0056761.s008", "https://dx.doi.org/10.1371/journal.pone.0056761.s009", "https://dx.doi.org/10.1371/journal.pone.0056761.s010", "https://dx.doi.org/10.1371/journal.pone.0056761.s011", "https://dx.doi.org/10.1371/journal.pone.0056761.s012", "https://dx.doi.org/10.1371/journal.pone.0056761.s013"], "stats"=>{"downloads"=>7, "page_views"=>21, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/Neoplastic_and_Stromal_Cells_Contribute_to_an_Extracellular_Matrix_Gene_Expression_Profile_Defining_a_Breast_Cancer_Subtype_Likely_to_Progress__/157316", "title"=>"Neoplastic and Stromal Cells Contribute to an Extracellular Matrix Gene Expression Profile Defining a Breast Cancer Subtype Likely to Progress", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2013-02-18 02:01:56"}
  • {"files"=>["https://ndownloader.figshare.com/files/487215"], "description"=>"<p>(A) Association between ECM3 grade III (ECM3 GIII, solid black line), non-ECM3 grade III (non-ECM3 GIII, dotted black line), ECM3 grade I–II (ECM3 GI-II, solid grey line) and non-ECM3 grade I–II (non-ECM3 GI-II, dotted grey line) with DMFS in untreated patient joined datasets. (B–E) Association between ECM3 (black line) and non-ECM3 (grey line) with DMFS in ER-negative grade I–II (B), ER-positive grade I–II (C), ER-negative grade III (D) and ER-positive grade III (E) subgroups. p-values by log rank test.</p>", "links"=>[], "tags"=>["prognostic", "differentiation"], "article_id"=>157727, "categories"=>["Biological Sciences", "Information And Computing Sciences", "Mathematics", "Cancer", "Molecular Biology", "Cell Biology"], "users"=>["Tiziana Triulzi", "Patrizia Casalini", "Marco Sandri", "Manuela Ratti", "Maria L. Carcangiu", "Mario P. Colombo", "Andrea Balsari", "Sylvie Menard", "Rosaria Orlandi", "Elda Tagliabue"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0056761.g004", "stats"=>{"downloads"=>0, "page_views"=>3, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_ECM3_prognostic_significance_in_relation_to_differentiation_status_/157727", "title"=>"ECM3 prognostic significance in relation to differentiation status.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-02-18 02:08:47"}

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Relative Metric

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