IMPACT OF AGE-ASSOCIATED CHANGES IN RET-INDUCED MAMMARY TUMOR DEVELOPMENT

CLARA DE LOS SANTOS; ROBERTO MEISS; EDITH C. KORDON; SABRINA VALLONE; ALBANA GATTELLI

Congreso; Reunión Anual SAIC 2023; 2023

SAIC

Most cancers arise in individuals over the age of 60-years old. As theworld population is living longer, cancer is becoming a substantialpublic health problem. Yet, the contribution of aging to oncogenicsignals is largely ignored, with most preclinical studies designed in2-month-old mice rather than older mice reflecting an age-appropriateto the disease being modeled.We study the oncogenic function of RET receptor tyrosine kinasein breast cancer. RET is overexpressed in 40% of breast tumorsrespect to normal tissue and high RET correlate with decreased survival.Using a doxycycline (DOX)-induced transgenic mouse system(RET/MTB), we previously demonstrated that RET expression inthe mammary epithelium induced estrogen receptor (ER) positivetumors, representing the human luminal subtype. Here, we aim toaddress the impact of aged microenvironment in the developmentof neoplastic lesions induced by RET. Firstly, we analyze mammarygland tissue from aged-virgin female mice. In addition to the reportedmorphological changes (histological analysis), we observe thataged glands (10 to 12-month-old, none cycling) express endogenousRET protein which is generally absent in young counterparts (2to 4-month-old). Interestingly, phosphorylation (p) pattern of RET aswell as ER, is differential: aged mammary gland displays high levelsof the pY1062RET fully glycosylated isoform and an increase in bothpS167ER and pS118ER (Western blot) respect to young mammarytissue. Then, we chronically DOX-induced RET overexpression inRET/MTB aged- vs. young-female’s groups. Surprisingly, we foundthat tumor incidence is reduced in older females (20%, 1/5) respectto younger females (62,5%, 5/8), suggesting an aged-related protectiverole against RET oncogene. Histology and signalling pathwaysare being analyzed in both epithelial tumor cells and adjacentmammary tissue microenvironment.