By screening a tissue microarray of invasive
breast tumors, we have shown that the
receptor tyrosine kinase RET (REarranged during Transfection) and its coreceptor GFR alpha 1 (
GDNF receptor family alpha-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 GFR alpha 1 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(+)/GFR alpha 1(+) 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-alpha and
interleukin-1 beta, 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 GFR alpha 1 receptors.