RET RECEPTOR TYROSINE KINASE CONTROLS MOUSE MAMMARY GLAND REMODELLING DURING THE POST-LACTATIONAL TRANSITION AND ITS DEREGULATION INCREASES CANCER POTENTIAL

RP. MEISS; EC. KORDON; S. VALLONE; LA. CHODOSH; A. GATTELLI; M. GARCÍA SOLÁ; N.E. HYNES

Bariloche

Simposio; SISTAM 2018; 2018

SISTAM

Loss of normal development is a hallmark of cancer. Thus, understanding the mechanisms of tissue-specific developmental regulation and the changes that occur during tumorigenesis may provide insights of both diagnostic and therapeutic importance. In breast cancer, several members of the receptor tyrosine kinases (RTK) family that are well known to promote aggressive breast cancers also have roles in normal breast. We found that endogenous Ret, a RTK member, is highly expressed in the mouse glands during transition to involution, a well know stage that drives cancer progression. Involution is the period with high inflammation which returns the lactating mammary gland to a quiescent state after weaning. Recently, using a doxycycline-inducible transgenic mouse model (Ret/MTB) we determined that chronic expression of Ret is oncogenic in the mammary epithelium. Ret is overexpressed in about 40% of human breast tumors. However, the stage of development at which Ret expression results in increase mammary tumor incidence has not been identified. To address this, we used the Ret/MTB system, to conditionally overexpress Ret during discrete periods of mammary gland development. We found that Ret is required for efficient transition to involution. We determined that the induction of Ret in Ret/MTB females promotes the expression of factors that drives involution, including Stat3 activation and specific inflammatory molecules identified by cytokine arrays. RNA-seq data in Ret-overexpressing glands is supporting these findings, which were confirmed by several techniques. In addition, sustained expression of Ret during post-lactation enhances cancer potential showing an increase in pre-neoplastic lesions, defective milk recycling and disrupting Stat3 signaling. These results demonstrate that Ret is essential for mammary gland post-lactational transition and its deregulation increases cancer potential.