Using mouse models of ER/PR-positive breast carcinomas, orthotopic xenografts of T47D human breast cancer cells, and clinical samples from breast cancer patients undergoing neoadjuvant endocrine therapy, we found that the intrinsic tumor heterogeneity for PI3K/Akt/mTOR activation as assessed by S6 protein phosphorylation is associated with therapeutic response. Here, ESR1 is linked to breast cancer.