Breast tumour stroma is a prognostic indicator and target for therapy

The development of the breast is exquisitely sensitive to interactions between the epithelium and stroma. Experimental evidence indicates that a reduction in signalling between any of the stromal cell types (fibroblasts, macrophages, endothelial cells and adipocytes) results in reduced or absent breast development [1], although all interactions appear to be orchestrated by the epithelial cell oestrogen receptor alpha [2]. The epithelial-stromal interactions that occur in tumours are less well characterised but there is no doubt there is expansion of the stroma as well as of the epithelium during tumour development [3,4]. Recent data indicate that the prognosis after breast cancer diagnosis relates to stromal type, and experimental and clinical studies directed at modifying the stroma (for example, angiogenesis inhibitors) suggest that the stroma is a target for therapy that is worthy of further exploration Studies of separately microdissected breast stroma and epithelium from normal lobules compared with ductal carcinoma in situ (DCIS) and invasive cancer indicate that extensive changes in gene expression in both the epithelial and stromal compartments occur during cancer development. These data strongly support the hypothesis that performing microdissections can be less optimal for gene expression profiling studies or to exclude cancers with a prominent stroma. Some array-based studies have had a requirement of more than 50% of cancer cells in the biopsies taken for array profiling; this may result in exclusion of biologically important cancers. Compared with the intralobular stroma of the normal breast lobule, Ma and colleagues reported that 2,338 genes were upregulated and 1,234 genes were downregulated in the stroma of DCIS [5]. A further 76 genes were upregulated and 229 genes were downregulated in the stroma of invasive tumours, indicating that most of the changes had occurred in DCIS suggesting that paracrine and endocrine influences are driving stroma formation rather than cell interactions, since the basement membrane is largely intact in DCIS. In a similar study examining stroma separated from the epithelium, Casey and colleagues demonstrated that the major changes of gene expression were upregulation of genes for the extracellular matrix and proteases in the stroma and downregulation of cytoskeletal proteins such as keratins, tubulins and adhesion molecules leading to increased cell motility in the tumour epithelium [6]. Invasive tumours have been likened to ‘wounds that do not heal’ [7]. In order to establish whether tumours induced gene expression similar to wounds, Chang and colleagues investigated whether they expressed the genes induced by serum in fibroblasts (the equivalent of wounding) [8,9]. The expression of 422 selected genes changed by serum in tumours was associated with a poor prognosis, whereas tumours with no change tended to have a good prognosis. In this study, although the genes were produced in serum-treated fibroblasts, they could have been expressed in epithelial cells of the tumours studied. In order to assess the prognostic and predictive significance of genes strictly of stromal origin, Finak and colleagues isolated stroma from normal lobules and tumours by laser capture microdissection, and derived a 26-gene expression signature that was a poor prognostic indicator irrespective of breast tumour subtype and standard prognostic indicators and that also indicated resistance to standard treatments [10]. The stromal signature, however, has been described to be associated with a basal type of breast cancer in three independent datasets, including the Canadian study [11]. Other gene signatures derived from the whole tumour and searched for potential stromal genes were also able to detect a poor prognosis signature [12] and to detect a stromal signature that indicated failure to respond to neoadjuvant 5-fluorouracil, epirubicin, and cyclophosphamide chemotherapy [13]. More recently two groups have demonstrated downregulation of a protein (caveolin-1) that acts as a scaffold protein in cell surface pits or caveolae (important for * Correspondence: Anthony.Howell@christie.nhs.uk Breakthrough Breast Cancer Research Unit, Paterson Institute for Cancer Research, University of Manchester, The Christie NHS Foundation Trust, University Hospital of South Manchester, Manchester M20 4BX, UK Howell et al. Breast Cancer Research 2009, 11:S16 http://breast-cancer-research.com/content/11/S3/S16

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