期刊
HISTOLOGY AND HISTOPATHOLOGY
卷 32, 期 7, 页码 687-698出版社
F HERNANDEZ
DOI: 10.14670/HH-11-830
关键词
Fatty acid syntase; HER2; Breast cancer; C75
资金
- Department of Defense award [W81XWH-06-1-0703]
- National Institutes of Health/National Cancer Institute award [R01-CA118975]
- Department of Energy [DE-AC03-76SF00098]
- Ministerio de Ciencia e Innovacion [SAF2012-38914]
- Plan Nacional de I+D+I, Spain
- Agencia de Gestio d'Ajuts Universitaris i de Recerca (AGAUR) [2014 SGR229]
- Departament d'Economia I Coneixement, Catalonia, Spain
Fatty acid synthase (FASN) is a key lipogenic enzyme for de novo fatty acid biosynthesis and a druggable metabolic oncoprotein that is activated in most human cancers. We evaluated whether the HER2-driven lipogenic phenotype might represent a biomarker for sensitivity to pharmacological FASN blockade. A majority of clinically HER2-positive tumors were scored as FASN overexpressors in a series of almost 200 patients with invasive breast carcinoma. Reclassification of HER2-positive breast tumors based on FASN gene expression predicted a significantly inferior relapse-free and distant metastasis-free survival in HER2+/FASN+ patients. Notably, non-tumorigenic MCF10A breast epithelial cells engineered to overexpress HER2 upregulated FASN gene expression, and the FASN inhibitor C75 abolished HER2-induced anchorage-independent growth and survival. Furthermore, in the presence of high concentrations of C75, HER2-negative MCF-7 breast cancer cells overexpressing HER2 (MCF-7/HER2) had significantly higher levels of apoptosis than HER2-negative cells. Finally, C75 at non-cytotoxic concentrations significantly reduced the capacity of MCF-7/HER2 cells to form mammospheres, an in vitro indicator of cancer stem-like cells. Collectively, our findings strongly suggest that the HER2-FASN lipogenic axis delineates a group of breast cancer patients that might benefit from treatment with therapeutic regimens containing FASN inhibitors.
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