GDNF-RET signaling in ER-positive breast cancers is a key determinant of response and resistance to aromatase inhibitors.
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Date
2013-06-15ICR Author
Author
Morandi, A
Martin, L-A
Gao, Q
Pancholi, S
Mackay, A
Robertson, D
Zvelebil, M
Dowsett, M
Plaza-Menacho, I
Isacke, CM
Type
Journal Article
Metadata
Show full item recordAbstract
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.
Subject
Cell Line, Tumor
Humans
Breast Neoplasms
Nitriles
Triazoles
Piperidines
Pyrimidines
Estradiol
Estrogen Receptor alpha
Aromatase Inhibitors
Protein Kinase Inhibitors
Blotting, Western
Oligonucleotide Array Sequence Analysis
Cell Culture Techniques
Cohort Studies
Gene Expression Profiling
Reverse Transcriptase Polymerase Chain Reaction
Signal Transduction
Cell Survival
Gene Expression Regulation, Neoplastic
RNA Interference
Drug Resistance, Neoplasm
Middle Aged
Female
Proto-Oncogene Proteins c-ret
Glial Cell Line-Derived Neurotrophic Factor
Kaplan-Meier Estimate
MCF-7 Cells
Fulvestrant
Letrozole
Research team
Molecular Cell Biology
Cancer Informatics
Endocrinology
Glioma Team
Language
eng
License start date
2013-06
Citation
Cancer research, 2013, 73 (12), pp. 3783 - 3795
Publisher
AMER ASSOC CANCER RESEARCH