Aberrant Ret expression causes mammary tumors and developmental defects during the post-lactational transition.

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

Weggis

Workshop; ENDBC meeting 2015; 2015

ENDBC

The receptor tyrosine kinase (RTK) Ret, a key oncoproteinin thyroid carcinomas due to its gain-of-function mutations, has also been implicatedin other types of cancers. Recently, Ret copy number gains and mutations havebeen reported at low frequencies in breast tumors. Furthermore, we and othershave reported that WT Ret is overexpressed in about 40% of human tumors andthis correlates with poor patient prognosis. Using a transgenic mouse model withthe MMTV promoter controlling Ret expression in the doxycycline-induciblesystem, we show that overexpression of WT Ret in the mammary epithelium produces hyperplasia and mammary tumorsdisplaying a solid morphology that recapitulates features of human solid ductalcarcinoma in situ. Moreover, Ret-induced tumors express ErbB2 and are estrogenreceptor positive. Importantly Ret-induced tumors rapidly regress after doxycyclinewithdrawal indicating that Ret is the driving oncoprotein. It is well knownthat RTKs, which are implicated in breast cancer, e.g. the ErbB receptors, alsohave 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 toinvolution since when Ret is induced early in lactation we observe enhancedkinetics of involution. The involution period is well known to drive cancerprogression. Thus, our results suggest that if Ret expression is deregulated duringthe lactation-involution transition this might contribute to breast cancerdevelopment.