Chronic expression of wild-type Ret receptor in the mammary gland induces luminal tumors that are sensitive to Ret inhibition

Abstract

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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Acknowledgements

We thank Dr. Giorgio Caravatti (Novartis Institutes for Biomedical Research, Basel, Switzerland) and all members of Hynes and Gattelli labs for helpful discussions.

Funding

AG was supported by grant KG101234 from Susan G. Komen for the Cure® and grant GF N° 02 from Fundación para el Progreso de la Medicina Córdoba. NEH was supported by grants from Susan G. Komen for the Cure® SAC110041, from Krebsliga beider Basel 10-2030 and by the Novartis Research Foundation.

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Correspondence to Albana Gattelli or Nancy E. Hynes.

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Gattelli, A., García Solá, M.E., Roloff, T.C. et al. Chronic expression of wild-type Ret receptor in the mammary gland induces luminal tumors that are sensitive to Ret inhibition. Oncogene 37, 4046–4054 (2018). https://doi.org/10.1038/s41388-018-0235-y

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