Targeting the receptor tyrosine kinase RET sensitizes breast cancer cells to tamoxifen treatment and reveals a role for RET in endocrine resistance.
Endocrine therapy is the main therapeutic option for patients with estrogen receptor (ERalpha)-positive breast cancer. Resistance to this treatment is often associated with estrogen-independent activation of ERalpha. In this study, we show that in ERalpha-positive breast cancer cells, activation of the receptor tyrosine kinase RET (REarranged during Transfection) by its ligand GDNF results in increased ERalpha phosphorylation on Ser118 and Ser167 and estrogen-independent activation of ERalpha transcriptional activity. Further, we identify mTOR as a key component in this downstream signaling pathway. In tamoxifen response experiments, RET downregulation resulted in 6.2-fold increase in sensitivity of MCF7 cells to antiproliferative effects of tamoxifen, whereas GDNF stimulation had a protective effect against the drug. In tamoxifen-resistant (TAM(R)-1) MCF7 cells, targeting RET restored tamoxifen sensitivity. Finally, examination of two independent tissue microarrays of primary human breast cancers revealed that expression of RET protein was significantly associated with ERalpha-positive tumors and that in primary tumors from patients who subsequently developed invasive recurrence after adjuvant tamoxifen treatment, there was a twofold increase in the number of RET-positive tumors. Together these findings identify RET as a potentially important therapeutic target in ERalpha-positive breast cancers and in particular in tamoxifen-resistant tumors.
Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, London, UK.
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I
Plaza-Menacho
A
A
Morandi
D
D
Robertson
S
S
Pancholi
S
S
Drury
M
M
Dowsett
L-A
LA
Martin
C M
CM
Isacke
D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D019008:Drug Resistance, Neoplasm; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism; D005260:Female; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D051096:Proto-Oncogene Proteins c-ret / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases; D013629:Tamoxifen / Q000031:analogs & derivatives / Q000494:pharmacology*
D018931:Antineoplastic Agents, Hormonal; D047628:Estrogen Receptor alpha; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors; D047908:Intracellular Signaling Peptides and Proteins; D013629:Tamoxifen; C016601:afimoxifene; C546842:MTOR protein, human; D051096:Proto-Oncogene Proteins c-ret; D017346:Protein Serine-Threonine Kinases; D058570:TOR Serine-Threonine Kinases