title: 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.affiliation: ProCURE (Program Against Cancer Therapeutic Resistance), Metabolism and Cancer Group, Catalan Institute of Oncology, Girona, Spain.|Girona Biomedical Research Institute (IDIBGI), Girona, Spain.
authors.forename: Bruna
authors.initials: B
authors.lastname: Corominas-Faja
authors.affiliation: IBYME, CONICET-Laboratorio de Immunohematología, Buenos Aires, Argentina.
authors.forename: Luciano
authors.initials: L
authors.lastname: Vellon
authors.affiliation: ProCURE (Program Against Cancer Therapeutic Resistance), Metabolism and Cancer Group, Catalan Institute of Oncology, Girona, Spain.|Girona Biomedical Research Institute (IDIBGI), Girona, Spain.
authors.forename: Elisabet
authors.initials: E
authors.lastname: Cuyàs
authors.affiliation: Girona Biomedical Research Institute (IDIBGI), Girona, Spain.
authors.forename: Maria
authors.initials: M
authors.lastname: Buxó
authors.affiliation: Girona Biomedical Research Institute (IDIBGI), Girona, Spain.|Unit of Clinical Research, Catalan Institute of Oncology, Girona, Spain.
authors.forename: Begoña
authors.initials: B
authors.lastname: Martin-Castillo
authors.affiliation: Department of Biochemistry and Molecular Biology, Facultat de Farmàcia, Universitat de Barcelona, Barcelona, Spain.|Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y la Nutrición (CIBEROBN), Instituto de Salud Carlos III, Madrid, Spain.
authors.forename: Dolors
authors.initials: D
authors.lastname: Serra
authors.affiliation: Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y la Nutrición (CIBEROBN), Instituto de Salud Carlos III, Madrid, Spain.|Departament de Química Orgànica, Facultat de Química, Institut de Biomedicina de la UB (IBUB), Universitat de Barcelona, Barcelona, Spain.
authors.forename: Jordi
authors.initials: J
authors.lastname: García
authors.affiliation: Mayo Clinic, Department of Laboratory Medicine and Pathology, Division of Experimental Pathology, Rochester, MN, USA.|Mayo Clinic Cancer Center, Rochester, MN, USA. lupu.ruth@mayo.edu.
authors.forename: Ruth
authors.initials: R
authors.lastname: Lupu
authors.affiliation: ProCURE (Program Against Cancer Therapeutic Resistance), Metabolism and Cancer Group, Catalan Institute of Oncology, Girona, Spain.|Girona Biomedical Research Institute (IDIBGI), Girona, Spain. jmenendez@idibgi.org jmenendez@iconcologia.net.
authors.forename: Javier A
authors.initials: JA
authors.lastname: Menendez
mesh_terms: D015107:4-Butyrolactone / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D054890:Fatty Acid Synthase, Type I / Q000037:antagonists & inhibitors / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D061986:MCF-7 Cells; D009857:Oncogenes / Q000235:genetics; D011379:Prognosis; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000187:drug effects / Q000235:genetics*; D016019:Survival Analysis
chemical_list: D015107:4-Butyrolactone; D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D054890:Fatty Acid Synthase, Type I; D018719:Erb-b2 Receptor Tyrosine Kinases; C406734:4-methylene-2-octyl-5-oxofuran-3-carboxylic acid; C518729:FASN protein, human; C508053:ERBB2 protein, human