Stromal gene expression predicts clinical outcome in breast cancer

Abstract

Although it is increasingly evident that cancer is influenced by signals emanating from tumor stroma, little is known regarding how changes in stromal gene expression affect epithelial tumor progression. We used laser capture microdissection to compare gene expression profiles of tumor stroma from 53 primary breast tumors and derived signatures strongly associated with clinical outcome. We present a new stroma-derived prognostic predictor (SDPP) that stratifies disease outcome independently of standard clinical prognostic factors and published expression-based predictors. The SDPP predicts outcome in several published whole tumor-derived expression data sets, identifies poor-outcome individuals from multiple clinical subtypes, including lymph node-negative tumors, and shows increased accuracy with respect to previously published predictors, especially for HER2-positive tumors. Prognostic power increases substantially when the predictor is combined with existing outcome predictors. Genes represented in the SDPP reveal the strong prognostic capacity of differential immune responses as well as angiogenic and hypoxic responses, highlighting the importance of stromal biology in tumor progression.

FZD7 has a critical role in cell proliferation in triple negative breast cancer

“…We found that 67% of TNBC samples expressed FZD7; whereas only 5% of non-TNBC samples expressed FZD7 (Figure 2b). We then studied FZD7 expression in a larger human breast tumor cohort reported by Finak et al We found that FZD7 mRNA expression was significantly higher in the TNBC samples (n ¼ 14) as compared with non-TNBC samples (n ¼ 109; P ¼ 0.0017, Wilcoxon test), consistent with the immunohistochemistry results (Supplementary Figure 4) (Finak et al, 2008). RT-PCR was then carried out to detect FZD7 expression in various breast cancer cell lines (Figure 2c The effect of FZD7 on the cell invasiveness was examined using an invasion assay.…”

Identification of PUMA as an estrogen target gene that mediates the apoptotic response to tamoxifen in human breast cancer cells and predicts patient outcome and tamoxifen responsiveness in breast cancer

“…Given that functional p53 is lost in the majority of human cancers, PUMA function is indeed compromised indirectly in these malignancies, with evidence that this impinges on the apoptotic response to irradiation and chemotherapeutic drugs (Yu and Zhang, 2005). More directly, loss of PUMA expression has been reported in melanomas (Karst et al, 2005), a proportion of Burkitt's lymphomas (Garrison et al, 2008), and interestingly, in the tumor stroma associated with breast carcinoma (Finak et al, 2008). However, the lack of spontaneous tumor formation in puma-knockout mice (Jeffers et al, 2003), and the paucity of studies showing reduced PUMA expression in cancer, suggests that it is not commonly directly inactivated during the tumorigenic process.…”

Microenvironnement tumoral

“…La description de l'aspect macroscopique d'une tumeur (consistance, dureté, limites, estimation de la taille), qui est étroitement lié au microenvironnement tumoral, est ainsi l'un des premiers temps diagnostiques pour le pathologiste. [10]. Cette signature stromale permet de classer les cancers du sein en catégories de bon ou de mauvais pronostic, indépendamment des facteurs pronostiques classiques tels que le grade histologique, la taille tumorale, le statut ganglionnaire ou l'expression des récepteurs hormonaux et de HER2 [10].…”

“…[10]. Cette signature stromale permet de classer les cancers du sein en catégories de bon ou de mauvais pronostic, indépendamment des facteurs pronostiques classiques tels que le grade histologique, la taille tumorale, le statut ganglionnaire ou l'expression des récepteurs hormonaux et de HER2 [10]. Le groupe de mauvais pronostic est caractérisé par une altération de l'expression de gènes impliqués dans l'angiogenèse, la réponse à l'hypoxie, l'activation des macrophages, ou la transition épithélio-mésenchymateuse.…”