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Neoplastic and stromal cells contribute to an extracellular matrix gene expression profile defining a breast cancer subtype likely to progress.

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, ?-estradiol induced ECM3 gene production in ER-positive breast carcinoma cell lines, whereas TGF? 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.

SUBMITTER: Triulzi T

PROVIDER: S-EPMC3575489 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Neoplastic and stromal cells contribute to an extracellular matrix gene expression profile defining a breast cancer subtype likely to progress.

Triulzi Tiziana T Casalini Patrizia P Sandri Marco M Ratti Manuela M Carcangiu Maria L ML Colombo Mario P MP Balsari Andrea A Ménard Sylvie S Orlandi Rosaria R Tagliabue Elda E

PloS one 20130218 2

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 ...[more]

PMID: 23441215

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Project description:The tumor microenvironment regulates tissue development and homeostasis, and its dysregulation contributes to neoplastic progression. Increased expression of type X collagen ?-1 (ColX?1) in tumor-associated stroma correlates with poor pathologic response to neoadjuvant chemotherapy in estrogen receptor (ER) and human epidermal growth factor receptor 2 (HER2)-positive breast cancers. Evaluation of ColX?1 expression patterns suggests a potential connection with elastin fibers. To investigate the possible interaction between ColX?1 and elastin, we evaluated the expression of ColX?1 in relation to elastin fibers in normal breast tissue, ductal carcinoma in situ, and invasive breast carcinomas at cellular and subcellular levels. Our findings demonstrate that ColX?1 colocalizes with elastin in invasive breast cancer-associated stroma by immunohistochemistry, immunofluorescence, and electron microscopy. In 212 invasive breast carcinomas, this complex was aberrantly and selectively expressed in tumor extracellular matrix in 79% of ER+/HER2-, 80% of ER+/HER2+, 76% of ER-/HER2+, and 58% of triple negative breast cancers. In contrast, ColX?1 was generally absent, while elastin was present perivascularly in normal breast tissue. ColX?1 and elastin were coexpressed in 58% of ductal carcinoma in situ (DCIS) in periductal areas. In mass-forming DCIS with desmoplastic stroma, the complex was intensely expressed in periductal areas as well as within the tumor-associated stroma in all cases. Our data suggest that the breast carcinoma neoplastic process may involve aberrant expression of ColX?1 and elastin in the tumor microenvironment emerging early at the DCIS stage. Enrichment of these complexes in tumor-associated stroma may represent a stromal signature indicative of intrinsic differences between breast cancers. These findings shed light on investigation into the role of aberrant collagen complex expression in tumorigenesis and tumor progression which may be leveraged in therapeutic and theranostic applications.

Dataset Information

Neoplastic and stromal cells contribute to an extracellular matrix gene expression profile defining a breast cancer subtype likely to progress.

Publications

Neoplastic and stromal cells contribute to an extracellular matrix gene expression profile defining a breast cancer subtype likely to progress.

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