| Autor: |
Gattelli A; Universidad de Buenos Aires (UBA), Facultad de Ciencias Exactas y Naturales, Buenos Aires, Argentina. albanaga@fbmc.fcen.uba.ar.; CONICET-UBA, Instituto de Fisiología, Biología Molecular y Neurociencias (IFIBYNE), 1428 CABA, Buenos Aires, Argentina. albanaga@fbmc.fcen.uba.ar.; Friedrich Miescher Institute for Biomedical Research (FMI), Maulbeerstrasse 66, CH-4058, Basel, Switzerland. albanaga@fbmc.fcen.uba.ar., García Solá ME; Universidad de Buenos Aires (UBA), Facultad de Ciencias Exactas y Naturales, Buenos Aires, Argentina.; CONICET-UBA, Instituto de Fisiología, Biología Molecular y Neurociencias (IFIBYNE), 1428 CABA, Buenos Aires, Argentina., Roloff TC; Friedrich Miescher Institute for Biomedical Research (FMI), Maulbeerstrasse 66, CH-4058, Basel, Switzerland., Cardiff RD; Pathology and Laboratory Medicine, Center for Genomic Pathology, School of Medicine, University of California Davis (UCD), County Rd. 98 & Hutchison Dr, Davis, USA., Kordon EC; Universidad de Buenos Aires (UBA), Facultad de Ciencias Exactas y Naturales, Buenos Aires, Argentina.; CONICET-UBA, Instituto de Fisiología, Biología Molecular y Neurociencias (IFIBYNE), 1428 CABA, Buenos Aires, Argentina., Chodosh LA; Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania (Upenn), 614 BRB II/III, 421 Curie Blvd, Philadelphia, USA., Hynes NE; Friedrich Miescher Institute for Biomedical Research (FMI), Maulbeerstrasse 66, CH-4058, Basel, Switzerland. Nancy.Hynes@fmi.ch.; University of Basel, CH-4002, Basel, Switzerland. Nancy.Hynes@fmi.ch. |
| Abstrakt: |
The receptor tyrosine kinase Ret, a key gain-of-function mutated oncoprotein in thyroid carcinomas, has recently been implicated in other cancer types. While Ret copy number gains and mutations have been reported at low frequencies in breast tumors, we and others have reported that Ret is overexpressed in about 40% of human tumors and this correlates with poor patient prognosis. Ret activation regulates numerous intracellular pathways related to proliferation and inflammation, but it is not known whether abnormal Ret expression is sufficient to induce mammary carcinomas. Using a novel doxycycline-inducible transgenic mouse model with the MMTV promoter controlling Ret expression, we show that overexpression of wild-type Ret in the mammary epithelium produces mammary tumors, displaying a morphology that recapitulates characteristics of human luminal breast tumors. Ret-evoked tumors are estrogen receptor positive and negative for progesterone receptor. Moreover, tumors rapidly regress after doxycycline withdrawal, indicating that Ret is the driving oncoprotein. Using next-generation sequencing, we examined the levels of transcripts in these tumors, confirming a luminal signature. Ret-evoked tumors have been passaged in mice and used to test novel therapeutic approaches. Importantly, we have determined that tumors are resistant to endocrine therapy, but respond successfully to treatment with a Ret kinase inhibitor. Our data provide the first compelling evidence for an oncogenic role of non-mutated Ret in the mammary gland and are an incentive for clinical development of Ret as a cancer biomarker and therapeutic target. |
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