Aberrant Ret receptor expression in the mammary gland causes tumors and developmental defects

TC. ROLOFF; EC.KORDON; A. GATTELLI; CM. PEROU; NE. HYNES ; RD. CARDIFF; LA. CHODOSH

Congreso; SAIC 2016; 2016

The receptor tyrosine kinase (RTK) Ret, a key oncoprotein in thyroid carcinomas due to gain-of-function mutations, has also been implicated in other types of cancers. Recently, Ret copy number gains and mutations have been reported at low frequencies in breast tumors. Furthermore, we and others have reported that Ret is overexpressed in about 40% of human tumors and this correlates with poor patient prognosis. Using a transgenic mouse model with the MMTV promoter controlling Ret expression in the doxycycline-inducible system, we show that overexpression of wild type (WT) Ret in the mammary epithelium produces hyperplasias and mammary tumors displaying a solid morphology that recapitulates features of human solid ductal carcinoma in situ. Moreover, Ret-induced tumors express ErbB2 and are estrogen receptor positive. Importantly Ret-induced tumors rapidly regress after doxycycline withdrawal indicating that Ret is the driving oncoprotein. Using next generation sequencing (NGS) we examined levels of transcripts in these tumors. We found that Stat signaling pathways could contribute to Ret-driven tumorigenesis. It is well known that RTKs, which are implicated in breast cancer, e.g. the ErbB receptors, also have roles in normal development. We found that Ret is highly expressed in mid-lactation. Indeed, Ret appears to have a role in the post-lactation transition to involution, where Stat pathways are crucial. Interestingly, when Ret is induced early in lactation we observe enhanced kinetics of involution. The involution period is well known to drive cancer progression. Thus, our results suggest that if Ret expression is deregulated during the lactation-involution transition this might contribute to breast cancer development.