Clinical and therapeutic relevance of the metabolic oncogene fatty acid synthase in HER2+ breast cancer.

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.

• 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)

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

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