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

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

CABA

Simposio; BA-BCS 2021; 2021

Ret is a receptor tyrosine kinase with oncogenic potentialin the mammary epithelium. Several receptorsdescribed as oncogenes in the breast have been shownto participate in specific developmental stages. We foundthat Ret is differentially expressed during mouse mammarygland development: Ret is present in lactation andits expression dramatically decreases in the followingperiod of involution, the stage during which the lactatinggland returns to a quiescent state after weaning. Basedon epidemiological and pre-clinical findings involution hasbeen described as a tumor promoting stage. Using theRet/MTB doxycycline-inducible mouse transgenic systemwe show that sustained expression of Ret in the mammaryepithelium during the post-lactation transition to involutionis accompanied by defects in tissue remodeling and an enhancementof cancer potential. Following constitutive Retexpression we observed a significant increase in microneoplasticlesions in the post-involuting versus the virginmammary glands. Furthermore, we show that abnormalRet overexpression during lactation promotes factors thatprime involution, including premature activation of Stat3signaling and by RNA-seq an acute phase inflammatoryresponse. Our results demonstrate that Ret contributes toa normal post-lactation transition and suggest that elevatedRet expression levels might be considered as a marker forpostpartum breast cancer development.