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

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

Ciocco

Congreso; Mammary Gland. Gordon Research Conference; 2022

Gordon Conferences

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 next 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 post-lactation transition to involution is accompanied by defects in tissue remodeling and an enhancement of cancer potential. We observed a significant increase in micro-neoplastic lesions in post-involuting mammary glands respect to virgin glands, following continuous Ret expression. Furthermore, we show that abnormal Ret overexpression during lactation promotes factors that prime involution, including premature activation of Stat3 signaling and those that trigger an acute phase inflammatory response as attested by RNA-seq data. Our results demonstrate that Ret contributes to post-lactation transition and suggest that Ret expression levels might be considered as a marker for postpartum breast cancer development.