These questions have provoked new mechanistic hypotheses that link resistance to endocrine agents to: (1) Specific defects in single strand break repair are associated with increased mortality from ER+ breast cancer [1,2]; (2) Loss/mutations of certain single strand break repair proteins that disrupt estrogen-regulated cell cycle control through the ATM, CHK2, CDK4 axis [1,2] thereby directly coupling endocrine therapy resistance to specific DNA repair defects; (3) Acquired mutations that drive metastasis include the generation of in-frame ESR1 gene fusions that activate epithelial-to-mesenchymal transition (EMT) driven metastasis as well as endocrine drug-resistant proliferation [3].