Abstract 4269: Opposite effect of ECM features in breast carcinoma progression according to tumor cell differentiation
Authors: Triulzi Tiziana , Sandri Marco , Casalini Patrizia , Aiello Piera , Balsari Andrea , Orlandi Rosaria , Tagliabue Elda 
Published: August 2012

Abstract
Our own recent analysis of extracellular matrix (ECM) gene expression profiles in breast carcinomas identified four different subgroups of breast tumors (ECM1, 2, 3 and 4) proposing a link between stroma composition and cancer progression (Bergamaschi et al. J. Pathol, 2008). Here, we further investigated the characteristics of ECM signature and its impact on tumor progression. The unsupervised clustering of 6 independent datasets, including more than 600 breast tumor samples, revealed that ECM3 was a robust cluster, presenting a homogeneous gene pattern that consistently allowed the identification of an independent group of tumors in all tested datasets. ECM3 is characterized by highly correlated over expression of 58 ECM genes encoding mainly structural proteins. From 26 to 41% of cases were ECM3-enriched and were mainly estrogen receptor-positive and low grade. Both tumor and stromal cells took part in the expression of ECM3 genes, and the hormonal and TGFβ stimuli appeared to highly contribute to ECM3 signature. Multivariate analysis of distant metastasis free survival (DMFS) in untreated breast carcinoma patients evidenced a statistically significant interaction between ECM3 and grade (p=0.0010), that is a different clinical significance in the subgroups grade I+II and grade III. Cox models estimated separately in the two groups indicated that ECM3 is strongly and significantly associated with worse survival probability only in grade III tumors (HR=3.0, 95% CI = 1.3 - 7.0, p=0.0098). It is noteworthy that the probability of developing metastases in a 10-year follow-up was 14% for ECM3 differentiated tumors (grade I+II) as compared to 61% for the ECM3 grade III carcinomas and about 25% for all non-ECM3 tumors. Moreover analysis of a data set of patients treated neoadjuvantly with chemotherapy revealed that, among the grade III tumors, pathological complete response was reached by 9% of ECM3 versus 74% of non-ECM3 tumors (p=0.04). In differentiated tumors no response difference was observed according to ECM. Gene set enrichment analysis (GSEA) according to tumor cells differentiation revealed that among grade III, non-ECM3 tumors were enriched for genes representative of NK, T and B cells, and involved in cell cycle progression, while EMT, TGFβ and hypoxia genes were significantly up-modulated in ECM3 tumors, suggesting that aggressiveness of ECM3 grade III tumors may reflect the lack of immune cell engagement and an increased invasive phenotype. Our results provide evidence that breast carcinoma progression and response to therapy are influenced by the interaction between tumor and stromal characteristics. (Partially supported by AIRC)
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4269. doi:1538-7445.AM2012-4269