No abstract

RET is a receptor tyrosine kinase with oncogenic potential in the mammary epithelium. Several receptors with oncogenic activity in the breast are known to participate in specific developmental stages. We found that RET is differentially expressed during mouse mammary gland development: RET is present in lactation and its expression dramatically decreases in involution, the period during which the lactating gland returns to a quiescent state after weaning. Based on epidemiological and pre-clinical findings, involution has been described as tumor promoting. Using the Ret/MTB doxycycline-inducible mouse transgenic system we show that sustained expression of RET in the mammary epithelium during the post-lactation transition to involution is accompanied by alterations in tissue remodeling and an enhancement of cancer potential. Following constitutive Ret expression we observed a significant increase in neoplastic lesions in the post-involuting versus the virgin mammary gland. Furthermore, we show that abnormal RET overexpression during lactation promotes factors that prime involution, including premature activation of Stat3 signaling and, using RNA-seq, an acute-phase inflammatory signature. Our results demonstrate that RET overexpression negatively affects the normal post-lactation transition.

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 Ret, a RTK member, is normally expressed in the mouse glands in lactation. We determined that inhibition of Ret activity in vivo does not alter lactation, however impacts in the transition to involution. Involution is the period with high inflammation which returns the lactating mammary gland to a quiescent state after weaning. Involution has been well described as a post-lactation stage that drives cancer progression. Ret is overexpressed in about 40% of human breast tumors. Previously, using a doxycycline-inducible transgenic mouse model (Ret/MTB) we determined that chronic expression of Ret is oncogenic in the mammary epithelium. 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 premature Stat3 activation. 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 a significant increase in pre-neoplastic lesions, defective milk recycling and disrupting Stat3 signaling. These results demonstrate that Ret deregulation increases cancer potential in post-lactation and might be considered as a prognostic marker for post-partum breast cancer. Citation Format: Sabrina A. Vallone, Martín García Solá, Robert D. Cardiff, Roberto P. Meiss, Lewis A. Chodosh, Carolina Shere-Levy, Edith C C. Kordon, Nancy E. Hynes, Albana Gattelli. Sustained Ret expression during mammary gland post-lactation induces premature involution and enhances cancer potential [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3685.