Endocrine therapy resistance: new insights

Abstract

The estrogen receptor positive (ER+) subset is the dominant contributor to global deaths from breast cancer which now exceeds 500,000 deaths annually. Lethality is driven by endocrine resistance, which has been shown to be associated with high mutational rates and extreme subclonal diversity. Treatment forces subclonal selection until the patient eventually succumbs to metastatic treatment-resistant disease. Recently, we have been addressing several questions related to this process: What is the cause of the increased mutation rate in lethal ER+ breast cancer? Why is endocrine therapy resistance related to mutational load? What are the functions of the somatic mutations that are eventually selected in the treatment resistant and metastatic clones? 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].