Abstract |
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. Re-classification 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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Authors | Bruna Corominas-Faja, Luciano Vellon, Elisabet Cuyàs, Maria Buxó, Begoña Martin-Castillo, Dolors Serra, Jordi García, Ruth Lupu, Javier A Menendez |
Journal | Histology and histopathology
(Histol Histopathol)
Vol. 32
Issue 7
Pg. 687-698
(Jul 2017)
ISSN: 1699-5848 [Electronic] Spain |
PMID | 27714708
(Publication Type: Journal Article)
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Chemical References |
- 4-methylene-2-octyl-5-oxofuran-3-carboxylic acid
- Antineoplastic Agents
- Enzyme Inhibitors
- FASN protein, human
- Fatty Acid Synthase, Type I
- ERBB2 protein, human
- Receptor, ErbB-2
- 4-Butyrolactone
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Topics |
- 4-Butyrolactone
(analogs & derivatives, pharmacology, therapeutic use)
- Antineoplastic Agents
(pharmacology)
- Apoptosis
(drug effects)
- Breast Neoplasms
(drug therapy, genetics)
- Cell Cycle
(drug effects)
- Cell Line, Tumor
- Enzyme Inhibitors
(pharmacology, therapeutic use)
- Fatty Acid Synthase, Type I
(antagonists & inhibitors, genetics)
- Female
- Gene Expression Regulation, Neoplastic
(drug effects)
- Humans
- MCF-7 Cells
- Oncogenes
(genetics)
- Prognosis
- Receptor, ErbB-2
(drug effects, genetics)
- Survival Analysis
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