TY - JOUR
T1 - Anastrozole Regulates Fatty Acid Synthase in Breast Cancer
AU - Cairns, Junmei
AU - Ingle, James N.
AU - Kalari, Krishna R.
AU - Goetz, Matthew P.
AU - Weinshilboum, Richard M.
AU - Gao, Huanyao
AU - Li, Hu
AU - Bari, Mehrab Ghanat
AU - Wang, Liewei
N1 - Funding Information:
This research was supported by the Breast Cancer Research Foundation (BCRF), NIH R01CA196648, UG1CA18967, P50CA116201 (Mayo Clinic Breast Cancer Specialized Program of Research Excellence), U1961388 (the Pharmacogenomics Research Network), the George M. Eisenberg Foundation for Charities, and the Nan Sawyer Breast Cancer Fund.
Funding Information:
J.N. Ingle reports grants from The Breast Cancer Research Foundation, NIHMayo Clinic Breast Cancer Specialized Program of Research Excellence, P50CA116201, The George M. Eisenberg Foundation for Charities, and The Nan Sawyer Breast Cancer Fund during the conduct of the study. M.P. Goetz reports other support from Eagle Pharmaceuticals, Eli Lilly, Biovica, Novartis; grants and other support from Sermonix, Pfizer, Eli Lilly; other support from Biotheranostics, AstraZeneca, Blueprint Medicines, Research to Practice, and Clinical Education Alliance outside the submitted work. R.M. Weinshilboum reports other support from OneOme LLC outside the submitted work. No disclosures were reported by the other authors.
Publisher Copyright:
© 2021 American Association for Cancer Research.
PY - 2022/1
Y1 - 2022/1
N2 - 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 6-month estrogen concentrations and risk of breast cancer. Anastrozole, but not exemestane or letrozole, is a ligand for estrogen receptor a. 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 the 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 MAPK pathway. High levels of FASN are associated with poor outcome only in patients with anastrozole-treated breast cancer, 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.
AB - 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 6-month estrogen concentrations and risk of breast cancer. Anastrozole, but not exemestane or letrozole, is a ligand for estrogen receptor a. 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 the 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 MAPK pathway. High levels of FASN are associated with poor outcome only in patients with anastrozole-treated breast cancer, 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.
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U2 - 10.1158/1535-7163.MCT-21-0509
DO - 10.1158/1535-7163.MCT-21-0509
M3 - Article
C2 - 34667110
AN - SCOPUS:85122957299
VL - 21
SP - 206
EP - 216
JO - Molecular Cancer Therapeutics
JF - Molecular Cancer Therapeutics
SN - 1535-7163
IS - 1
ER -