This Article Full Text Full Text (PDF) Supplementary Data Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Esseghir, S. Articles by Isacke, C. M. Search for Related Content PubMed PubMed Citation Articles by Esseghir, S. Articles by Isacke, C. M.

A Role for Glial Cell–Derived Neurotrophic Factor–Induced Expression by Inflammatory Cytokines and RET/GFR1 Receptor Up-regulation in Breast Cancer

¹ Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research and ² In Situ Hybridisation Service and Histopathology Unit, Cancer Research UK-London Research Institute, London, United Kingdom

Requests for reprints: Clare M. Isacke, Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, United Kingdom. Phone: 44-20-7153-5510; Fax: 44-20-7153-5340; E-mail: clare.isacke{at}icr.ac.uk.

By screening a tissue microarray of invasive breast tumors, we have shown that the receptor tyrosine kinase RET (REarranged during Transfection) and its coreceptor GFR1 (GDNF receptor family -1) are overexpressed in a subset of estrogen receptor–positive tumors. Germ line–activating oncogenic mutations in RET allow this receptor to signal independently of GFR1 and its ligand glial cell–derived neurotrophic factor (GDNF) to promote a spectrum of endocrine neoplasias. However, it is not known whether tumor progression can also be driven by receptor overexpression and whether expression of GDNF, as has been suggested for other neurotrophic factors, is regulated in response to the inflammatory microenvironment surrounding many epithelial cancers. Here, we show that GDNF stimulation of RET⁺/GFR1⁺ MCF7 breast cancer cells in vitro enhanced cell proliferation and survival, and promoted cell scattering. Moreover, in tumor xenografts, GDNF expression was found to be up-regulated on the infiltrating endogenous fibroblasts and to a lesser extent by the tumor cells themselves. Finally, the inflammatory cytokines tumor necrosis factor- and interleukin-1β, which are involved in tumor promotion and development, were found to act synergistically to up-regulate GDNF expression in both fibroblasts and tumor cells. These data indicate that GDNF can act as an important component of the inflammatory response in breast cancers and that its effects are mediated by both paracrine and autocrine stimulation of tumor cells via signaling through the RET and GFR1 receptors. [Cancer Res 2007;67(24):11732–41]