Aberrant Ret expression impacts on normal mammary gland post-lactation transition enhancing cancer potential

Sabrina A. Vallone¹, Martín García Solá¹, Roberto P. Meiss¹, Robert D. Cardiff², Lewis A. Chodosh³, Carolina Schere-Levy¹, Nancy E. Hynes⁴, Edith C. Kordon¹, Albana Gattelli¹

Ret is a receptor tyrosine kinase with oncogenic potential in the mammary epithelium. Several receptors described as oncogenes in the breast have been shown 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 the following period of involution, the stage during which the lactating gland returns to a quiescent state after weaning. Based on epidemiological and pre-clinical findings involution has been described as a tumor promoting stage. 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 defects in tissue remodeling and an enhancement of cancer potential. Following constitutive Ret expression we observed a significant increase in micro-neoplastic lesions in the post-involuting versus the virgin mammary glands. Furthermore, we show that abnormal Ret overexpression during lactation promotes factors that prime involution, including premature activation of Stat3 signaling and by RNA-seq an acute phase inflammatory response. Our results demonstrate that Ret contributes to a normal post-lactation transition and suggest that elevated Ret expression levels might be considered as a marker for postpartum breast cancer development.