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

GATTELLI A.; CARDIFF R.D; CHODOSH L.A; HYNES N. E.

Sow Mount

Seminario; Gordon Research Seminars in Mammary Gland; 2015

Gordon Reserch Conferences

The receptor tyrosine kinase (RTK) Ret,a key oncoprotein in thyroid carcinomas due to gain-of-function mutations, has alsobeen implicated in other types of cancers. Recently, Ret copy number gains andmutations have been reported at low frequencies in breast tumors. Furthermore,we and others have reported that WT Ret is overexpressed in about 40% of humantumors and this correlates with poor patient prognosis. Using a transgenic mousemodel with the MMTV promoter controlling Ret expression in thedoxycycline-inducible system, we show that overexpression of  WT Ret in the mammary epithelium produceshyperplasias and mammary tumors displaying a solid morphology that recapitulatesfeatures of human solid ductal carcinoma in situ. Moreover, Ret-induced tumorsexpress ErbB2 and are estrogen receptor positive. Importantly Ret-inducedtumors rapidly regress after doxycycline withdrawal indicating that Ret is thedriving oncoprotein. Using next generation sequencing (NGS) we examined levelsof transcripts in these tumors. We found that ErbB2/Akt and Stat signalingpathways 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 rolesin normal development. We found that Ret is highly expressed in mid-lactation.Indeed, Ret appears to have a role in the post-lactation transition toinvolution, where Stat pathways are crucial. Interestingly, when Ret is inducedearly in lactation we observe enhanced kinetics of involution. The involutionperiod is well known to drive cancer progression. Thus, our results suggest thatif Ret expression is deregulated during the lactation-involution transitionthis might contribute to breast cancer development.