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

EDITH KORDON; ALBANA GATTELLI; MARTÍN GARCÍA SOLÁ; TOM ROLOFF; ROBERT CARDIFF; LEWIS CHODOSH; NANCY E. HYNES

ONCOGENE

NATURE PUBLISHING GROUP

Año: 2018

0950-9232

Receptor tyrosine kinase, breast cancer, transgenic mouse, Ret, mTorThe receptor tyrosine kinase Ret, a key gain-of-function mutated oncoprotein inthyroid carcinomas, has recently been implicated in other cancer types. While Retcopy number gains and mutations have been reported at low frequencies in breasttumors, we and others have reported that Ret is overexpressed in about 40% ofhuman tumors and this correlates with poor patient prognosis. Ret activationregulates numerous intracellular pathways related to proliferation andinflammation, but it is not known whether abnormal Ret expression is sufficient toinduce mammary carcinomas. Using a novel doxycycline-inducible transgenicmouse model with the MMTV promoter controlling Ret expression, we show thatoverexpression of wild type Ret in the mammary epithelium produces mammarytumors displaying a morphology that recapitulates characteristics of human luminalbreast tumors. Ret-evoked tumors are estrogen receptor positive and negative forprogesterone receptor. Moreover, tumors rapidly regress after doxycyclinewithdrawal indicating that Ret is the driving oncoprotein. Using next generationsequencing we examined the levels of transcripts in these tumors, confirming aluminal signature. Ret-evoked tumors have been passaged in mice and used totest novel therapeutic approaches. Importantly, we have determined that tumorsare resistant to endocrine therapy, but respond successfully to treatment with a Retkinase inhibitor. Our data provide the first compelling evidence for an oncogenicrole of non-mutated Ret in the mammary gland and are an incentive for clinicaldevelopment of Ret as a cancer biomarker and therapeutic target.