Anastrozole regulates fatty acid synthase in breast cancer.

Our previous matched case-control study of postmenopausal women with resected early stage breast cancer revealed that only anastrozole, but not exemestane or letrozole, showed a significant association between the six-month estrogen concentrations and risk of breast cancer event. Anastrozole, but not exemestane or letrozole, is a ligand for estrogen receptor α (ERα). The mechanisms of endocrine resistance are heterogenous and with the new mechanism of anastrozole, we have found that treatment of anastrozole maintains fatty acid synthase (FASN) protein level by limiting the ubiquitin-mediated FASN degradation, leading to increased breast cancer cell growth. Mechanistically, anastrozole decreases guided entry of tail-anchored proteins factor 4 (GET4) expression, resulting in decreased BCL2-associated athanogene cochaperone 6 (BAG6) complex activity, which in turn, prevents RNF126-mediated degradation of FASN. Increased FASN protein level can induce a negative feedback loop mediated by the mitogen-activated protein kinase (MAPK) pathway. High levels of FASN are associated with poor outcome only in anastrozole-treated breast cancer patients, but not in patients treated with exemestane or letrozole. Repressing FASN causes regression of breast cancer cell growth. The anastrozole-FASN signaling pathway is eminently targetable in endocrine-resistant breast cancer.