To recapitulate mTORi resistance acquisition occurring in breast cancer patients in a more appropriate way, we analyzed mammary tumors isolated from immunocompetent mice that were enrolled into a long-term mTORi intervention, we made use of clinically approved mTOR-targeted therapies, and we engaged in mouse modeling using tumor samples of mouse and human origin to functionally pinpoint MYC as an in vivo driver of mTORi resistance. This evidence concerns the gene MTOR and breast cancer.