Determination of Stromal Signatures in Breast Carcinoma

Abstract

Many soft tissue tumors recapitulate features of normal connective tissue. We hypothesize that different types of fibroblastic tumors are representative of different populations of fibroblastic cells or different activation states of these cells. We examined two tumors with fibroblastic features, solitary fibrous tumor (SFT) and desmoid-type fibromatosis (DTF), by DNA microarray analysis and found that they have very different expression profiles, including significant differences in their patterns of expression of extracellular matrix genes and growth factors. Using immunohistochemistry and in situ hybridization on a tissue microarray, we found that genes specific for these two tumors have mutually specific expression in the stroma of nonneoplastic tissues. We defined a set of 786 gene spots whose pattern of expression distinguishes SFT from DTF. In an analysis of DNA microarray gene expression data from 295 previously published breast carcinomas, we found that expression of this gene set defined two groups of breast carcinomas with significant differences in overall survival. One of the groups had a favorable outcome and was defined by the expression of DTF genes. The other group of tumors had a poor prognosis and showed variable expression of genes enriched for SFT type. Our findings suggest that the host stromal response varies significantly among carcinomas and that gene expression patterns characteristic of soft tissue tumors can be used to discover new markers for normal connective tissue cells.

The fibromatosis signature defines a robust stromal response in breast carcinoma

“…17 In a proof-of-principle study, we used gene expression profiles from two different fibroblastic soft-tissue tumors, desmoid-type fibromatosis (DTF) and solitary fibrous tumor (SFT), to identify new subtypes of tumor stroma. 15 In comparing the SFT and DTF gene expression profiles, we found a remarkably large number of differentially expressed genes. One of the more striking differences was in the variation of genes involved in the fibrotic response and basement membrane synthesis.…”

“…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.…”

“…We examined the expression patterns of DTF-and SFT-associated genes in a large publically available breast cancer data set from the Netherlands Cancer Institute (NKI), 18 and showed that the subset of breast cancers with high levels of coordinated expression of DTF-associated genes demonstrated significantly better outcome, and tumors identified by elevated levels of expression of SFT-associated genes had a much worse outcome. 15 Due to the high dimensionality of gene array data, associations between elevated levels of expression for a group of genes with outcome should be interpreted with caution. 19 In fact, results from a number of expression profiling papers could not be reproduced on separate data sets, 20 and there is consensus in the biomedical community that demonstrating reproducibility of gene-expression signatures in independent data sets is essential for establishing their robustness and validity.…”

Le microenvironnement tumoral

“…Un degré de complexité supplémen-taire est apporté par l'intervention du microenvironnement tumoral qui interagit avec les cellules cancéreuses et modifie plusieurs aspects du développe-ment tumoral, notamment la croissance, l'angiogenèse, l'invasion, la formation de métastases, ainsi que l'échappe-ment immunitaire [5][6][7]. Toutefois, peu d'études génomiques à grande échelle à partir d'échantillons cliniques de cancer du sein ont évalué l'impact du microenvironnement tumoral sur le pronostic [8][9][10].Identification d'une signature moléculaire prédictive spécifique des modifications du stroma tumoral Nous avons entrepris l'une des premières études de ce genre [11]. À cette fin, nous avons appliqué à 53 tumeurs du sein primaires (carcinome canalaire infiltrant) une approche de microdissection par capture au laser afin d'isoler successivement, chez une même patiente, les cellules stromales qui entourent la tumeur, ainsi que des cellules du tissu normal ( Figure 1A) [12].…”

“…Un degré de complexité supplémen-taire est apporté par l'intervention du microenvironnement tumoral qui interagit avec les cellules cancéreuses et modifie plusieurs aspects du développe-ment tumoral, notamment la croissance, l'angiogenèse, l'invasion, la formation de métastases, ainsi que l'échappe-ment immunitaire [5][6][7]. Toutefois, peu d'études génomiques à grande échelle à partir d'échantillons cliniques de cancer du sein ont évalué l'impact du microenvironnement tumoral sur le pronostic [8][9][10].…”