Extracellular matrix signature identifies breast cancer subgroups with different clinical outcome

Abstract

Prediction of the clinical outcome of breast cancer is multi-faceted and challenging. There is growing evidence that the complexity of the tumour micro-environment, consisting of several cell types and a complex mixture of proteins, plays an important role in development, progression, and response to therapy. In the current study, we investigated whether invasive breast tumours can be classified on the basis of the expression of extracellular matrix (ECM) components and whether such classification is representative of different clinical outcomes. We first examined the matrix composition of 28 primary breast carcinomas by morphology and gene expression profiling using 22K oligonucleotide Agilent microarrays. Hierarchical clustering of the gene expression profile of 278 ECM-related genes derived from the literature divided the tumours into four main groups (ECM1-4). A set of selected differentially expressed genes was validated by immunohistochemistry. The robustness of the ECM classification was confirmed by studying the four ECM groups in a previously published gene expression data set of 114 early-stage primary breast carcinomas profiled using cDNA arrays. Univariate survival analysis showed significant differences in clinical outcome among the various ECM subclasses. One set of tumours, designated ECM4, had a favourable outcome and was defined by the overexpression of a set of protease inhibitors belonging to the serpin family, while tumours with an ECM1 signature had a poorer prognosis and showed high expression of integrins and metallopeptidases, and low expression of several laminin chains. Furthermore, we identified three surrogate markers of ECM1 tumours: MARCO, PUNC, and SPARC, whose expression levels were associated with breast cancer survival and risk of recurrence. Our findings suggest that primary breast tumours can be classified based upon ECM composition and that this classification provides relevant information on the biology of breast carcinomas, further supporting the hypothesis that clinical outcome is strongly related to stromal characteristics.

In vivo MRI and histopathological assessment of tumor microenvironment in luminal‐like and basal‐like breast cancer xenografts

“…Studies of the stroma composition of the luminal-like and basal-like xenograft models have shown different extracellular matrix (ECM) signatures corresponding to the ECM subgroups 2 and 1, respectively (4). The low ADC values found in the luminal-like tumors are in agreement with the high content of collagen and fibronectin in the stroma of the ECM subgroup 2 (5). A large extracellular space crammed with proteins will serve as a reservoir of contrast agent molecules.…”

“…A better understanding of the tumor biology and microenvironment characteristics related to different breast cancer subtypes and the extracellular matrix composition may assist in the prediction of biologic and therapeutic responses and thereby improved treatment strategies and more individual patient management (4,5). Host-derived factors such as the endothelial cells and the vascular system constitute an important part of the tumor microenvironment and are essential during angiogenesis.…”

The extracellular matrix in breast cancer predicts prognosis through composition, splicing, and crosslinking

“…These tumors tend to show complete loss of laminin and high levels of vascularization, which may explain some of the linkage between this form of ECM and poor outcome [61]. Stiff tumors, measured with ultrasound elastography, tend to be the most aggressive types, including triple negative or Her2 þ tumors [62].…”

“…Stiff tumors, measured with ultrasound elastography, tend to be the most aggressive types, including triple negative or Her2 þ tumors [62]. High levels of hyaluronic acid appears linked to HER2 þ cancers, which tend to be more aggressive [61]. Patients with lumican and decorin polymorphisms appear to develop more ER þ cancers [45], which usually have better prognosis.…”

The fibromatosis signature defines a robust stromal response in breast carcinoma

“…9,10 Most studies of tumor stroma consider it as a relatively uniform entity, and the contribution of inter-patient stromal variability to the biological and clinical heterogeneity of breast cancer is only beginning to be recognized and understood. [11][12][13][14][15][16] We hypothesize that within a particular group of tumors (eg, breast carcinoma) there exist distinct types of stromal reaction patterns that affect tumor growth in different ways. We propose that fibroblastic soft-tissue tumors, which are thought to be clonal outgrowths derived from distinct subtypes or precursors of fibroblasts, and which yield relatively pure and consistent gene expression profiles, can function as discovery tools for identifying distinct fibroblastic reaction patterns.…”