Tumor and Stem Cell Biology GDNF–RET Signaling in ER-Positive Breast Cancers Is a Key Determinant of Response and Resistance to Aromatase Inhibitors

Most breast cancers at diagnosis are estrogen receptor-positive (ERþ) and depend on estrogen for growth and survival. Blocking estrogen biosynthesis by aromatase inhibitors has therefore become a first-line endocrine therapy for postmenopausal women with ERþ breast cancers. Despite providing substantial improvements in patient outcome, aromatase inhibitor resistance remains amajor clinical challenge. The receptor tyrosine kinase, RET, and its coreceptor, GFRa1, are upregulated in a subset of ERþ breast cancers, and the RET ligand, glialderived neurotrophic factor (GDNF) is upregulated by inflammatory cytokines. Here, we report the findings of a multidisciplinary strategy to address the impact of GDNF–RET signaling in the response to aromatase inhibitor treatment. In breast cancer cells in two-dimensional and three-dimensional culture, GDNF-mediated RET signaling is enhanced in amodel of aromatase inhibitor resistance. Furthermore, GDNF–RET signaling promoted the survival of aromatase inhibitor-resistant cells and elicited resistance in aromatase inhibitor-sensitive cells. Both these effectswere selectively reverted by the RETkinase inhibitor, NVP-BBT594. Gene expression profiling in ERþ cancers defined a proliferation-independent GDNF response signature that prognosed poor patient outcome and, more importantly, predicted poor response to aromatase inhibitor treatment with the development of resistance. We validated these findings by showing increased RET protein expression levels in an independent cohort of aromatase inhibitor-resistant patient specimens. Together, our results establish GDNF–RET signaling as a rational therapeutic target to combat or delay the onset of aromatase inhibitor resistance in breast cancer. Cancer Res; 73(12); 1–13. 2013 AACR.