Finak, G. et al. Stromal gene expression predicts clinical outcome in breast cancer. Nat. Med. 14, 518-527

McGill Centre for Bioinformatics, 3775 University Street, McGill University, Québec H3A 2B4, Canada.
Nature medicine (Impact Factor: 27.36). 06/2008; 14(5):518-27. DOI: 10.1038/nm1764
Source: PubMed


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.

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    • "Fig. 3. IL-11 is elevated in breast cancer tissue irrespective of grade or hormone receptor status. (A) 'Gluck' [119] and (B) 'Finak' [120] Oncomine data is presented. *P < 0.05, **P < 0.001, ***P < 0.001. "
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    ABSTRACT: Interleukin (IL)-11 is a member of the IL-6 family of cytokines that is defined by the shared use of the GP130 signal transducing receptor subunit. In addition of its long recognized activities as a hemopoietic growth factor, IL-11 has an emerging role in epithelial cancer biology. Through the activation of the GP130-Janus kinase signaling cascade and associated transcription factor STAT3, IL-11 can confer many of the tumor intrinsic 'hallmark' capabilities to neoplastic cells, if they express the ligand-specific IL-11Rα receptor subunit. Accordingly, IL-11 signaling has recently been identified as a rate-limiting step for the growth tumors arising from the mucosa of the gastrointestinal tract. However, there is less appreciation for a potential role of IL-11 to support breast cancer progression, apart from its well documented capacity to facilitate bone metastasis. Here we review evidence that IL-11 expression in breast cancer correlates with poor disease outcome and discuss some of the molecular mechanisms that are likely to underpin these observations. These include the capacity of IL-11 to stimulate survival and proliferation of cancer cells alongside angiogenesis of the primary tumor and of metastatic progenies at distant organs. We review current strategies to interfere with IL-11 signaling and advocate that inhibition of IL-11 signaling may represent an emerging therapeutic opportunity for numerous cancers. Copyright © 2015. Published by Elsevier Ltd.
    Preview · Article · Jul 2015 · Cytokine & growth factor reviews
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    • "RESULTS CDCP1 Is Overexpressed in Primary and Metastatic Human Breast Tumors, and CDCP1/HER2 Expression Correlates with Poor Patient Prognosis Recent studies have highlighted the role of CDCP1 in multiple human cancers (Wortmann et al., 2009). To investigate whether CDCP1 is overexpressed in human breast cancer, we first analyzed CDCP1 mRNA levels in three independent human breast cancer data sets (Finak, n = 59; TCGA, n = 450; and Curtis, n = 1,700) (Cancer Genome Atlas Network, 2012; Curtis et al., 2012; Finak et al., 2008), and found that in all three data sets CDCP1 was significantly overexpressed in human breast cancer compared with normal tissues (Figure 1A). To validate the protein level of CDCP1 in human breast cancer tissues, we first established CDCP1 immunohistochemistry (IHC) staining in a cell line expressing control or CDCP1 vectors (Figures S1A and S1B). "
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    ABSTRACT: Understanding the molecular pathways that contribute to the aggressive behavior of HER2-positive breast cancers may aid in the development of novel therapeutic interventions. Here, we show that CDCP1 and HER2 are frequently co-overexpressed in metastatic breast tumors and associated with poor patient prognosis. HER2 and CDCP1 co-overexpression leads to increased transformation ability, cell migration, and tumor formation in vivo, and enhanced HER2 activation and downstream signaling in different breast cancer cell lines. Mechanistically, we demonstrate that CDCP1 binds to HER2 through its intracellular domain, thereby increasing HER2 interaction with the non-receptor tyrosine kinase c-SRC (SRC), leading to trastuzumab resistance. Taken together, our findings establish that CDCP1 is a modulator of HER2 signaling and a biomarker for the stratification of breast cancer patients with poor prognosis. Our results also provide a rationale for therapeutic targeting of CDCP1 in HER2-positive breast cancer patients. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
    Full-text · Article · Apr 2015 · Cell Reports
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    • "Recent data have shown that the initiation, development and homeostasis of most solid malignancies are not only related to tumor intrinsic features, but also to features related to the tumor microenvironment [7] [14] [23] [25] [83]. An increase of the stromal compartment within the cancer mass has been associated with worse disease outcome and increased cancer metastasis [34] [44] [47] [48]. "

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