Sustained Ret expression during mammary gland post-lactation induces premature involution and enhances cancer potential

SABRINA A. VALLONE; MARTÍN GARCÍA SOLÁ; ROBERT D. CARDIFF; ROBERTO P. MEISS; LEWIS A. CHODOSH; SCHERE LEVY CAROLINA; EDITH C. KORDON; NANCY E. HYNES; ALBANA GATTELLI

San Diego

Congreso; AACR Anual meeting 2020; 2020

AACR

Loss of normal development is a hallmark of cancer. Thus, understanding the mechanisms of tissue-specific developmental regulation and the changes that occurduring 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 Ret, a RTK member, is normally expressed in themouse glands in lactation. We determined that inhibition of Ret activity in vivo does not alter lactation, however impacts in the transition to involution. Involution isthe period with high inflammation which returns the lactating mammary gland to a quiescent state after weaning. Involution has been well described as a postlactation stage that drives cancer progression. Ret is overexpressed in about 40% of human breast tumors. Previously, using a doxycycline-inducible transgenic mousemodel (Ret/MTB) we determined that chronic expression of Ret is oncogenic in the mammary epithelium. However, the stage of development at which Ret expressionresults in increase mammary tumor incidence has not been identified. To address this, we used the Ret/MTB system, to conditionally overexpress Ret during discreteperiods of mammary gland development. We found that Ret is required for efficient transition to involution. We determined that the induction of Ret in Ret/MTBfemales promotes the expression of factors that drives involution, including premature Stat3 activation. RNA-seq data in Ret-overexpressing glands is supportingthese findings, which were confirmed by several techniques. In addition, sustained expression of Ret during post-lactation enhances cancer potential showing asignificant increase in pre-neoplastic lesions, defective milk recycling and disrupting Stat3 signaling. These results demonstrate that Ret deregulation increases cancerpotential in post-lactation and might be considered as a prognostic marker for post-partum breast cancer.