Most cancers arise in individuals over 60 and, as the global population ages, cancer is becoming a significant public health problem. Yet, the contribution of aging to oncogenic signals is largely ignored, with most preclinical studies designed in 2-month-old mice rather than older mice reflecting an age appropriate to the disease being modeled. 
For several years, our lab has been studying the oncogenic function of RET receptor tyrosine kinase in breast cancer. RET is overexpressed in 40% of breast tumors with respect to normal tissue and high RET correlates with decreased survival. Using a doxycycline (DOX)-induced transgenic mouse system (RET/MTB), we previously demonstrated that RET expression in the mammary epithelium-induced estrogen receptor (ER) positive tumors, representing the human luminal subtype. Here, we aim to address the impact of aged microenvironment in the development of neoplastic lesions induced by RET. Firstly, we analyze mammary gland tissue from aged-virgin female mice. In addition to the reported morphological changes (histological analysis), we observe that aged glands (10 to 12-month-old, none cycling) express endogenous RET protein which is generally absent in young counterparts (2 to 4-month-old). Interestingly, phosphorylation (p) pattern of RET as well as ER, is differential: aged mammary gland displays high levels of the pY1062RET fully glycosylated isoform and a significant increase in pS118ER (Western blot) with respect to young mammary tissue. Then, we chronically DOX-induced RET overexpression in RET/MTB aged- vs. young-female groups. Surprisingly, we found that tumor incidence is reduced in older females (20%, 1/5) with respect to younger females (62,5%, 5/8), suggesting an aged-related protective role against RET oncogene. Signaling pathways activated by RET were analyzed in both epithelial tumor cells and adjacent mammary tissue microenvironment.