title: GDNF-RET signaling in ER-positive breast cancers is a key determinant of response and resistance to aromatase inhibitors.
abstract: Most breast cancers at diagnosis are estrogen receptor-positive (ER(+)) 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 ER(+) breast cancers. Despite providing substantial improvements in patient outcome, aromatase inhibitor resistance remains a major clinical challenge. The receptor tyrosine kinase, RET, and its coreceptor, GFRα1, are upregulated in a subset of ER(+) breast cancers, and the RET ligand, glial-derived 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 a model 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 effects were selectively reverted by the RET kinase inhibitor, NVP-BBT594. Gene expression profiling in ER(+) 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.
authors: Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, Department of Academic Biochemistry, The Royal Marsden Hospital; and London Research Institute, Cancer Research UK, London, United Kingdom.
authors: Andrea
authors: A
authors: Morandi
authors: Lesley-Ann
authors: LA
authors: Martin
authors: Qiong
authors: Q
authors: Gao
authors: Sunil
authors: S
authors: Pancholi
authors: Alan
authors: A
authors: Mackay
authors: David
authors: D
authors: Robertson
authors: Marketa
authors: M
authors: Zvelebil
authors: Mitch
authors: M
authors: Dowsett
authors: Ivan
authors: I
authors: Plaza-Menacho
authors: Clare M
authors: CM
authors: Isacke
mesh_terms: D047072:Aromatase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D018929:Cell Culture Techniques / Q000379:methods; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D015331:Cohort Studies; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics; D004958:Estradiol / Q000031:analogs & derivatives / Q000494:pharmacology; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism; D005260:Female; D000077267:Fulvestrant; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D053208:Kaplan-Meier Estimate; D000077289:Letrozole; D061986:MCF-7 Cells; D008875:Middle Aged; D009570:Nitriles / Q000494:pharmacology / Q000627:therapeutic use; D020411:Oligonucleotide Array Sequence Analysis; D010880:Piperidines / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051096:Proto-Oncogene Proteins c-ret / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011743:Pyrimidines / Q000494:pharmacology; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects* / Q000235:genetics; D014230:Triazoles / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D047072:Aromatase Inhibitors; D047628:Estrogen Receptor alpha; D051100:Glial Cell Line-Derived Neurotrophic Factor; C583136:NVP-BBT594; D009570:Nitriles; D010880:Piperidines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D014230:Triazoles; D000077267:Fulvestrant; D004958:Estradiol; D000077289:Letrozole; D051096:Proto-Oncogene Proteins c-ret; C099282:RET protein, human
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