Fatty acid oxidation is associated with proliferation and prognosis in breast and other cancers

Aziz Aiderus, Michael A. Black, Anita K. Dunbier

Altered cellular metabolism is a hallmark of cancer but the association between utilisation of particular metabolic pathways in tumours and patient outcome is poorly understood. We sought to investigate the association between fatty acid metabolism and outcome in breast and other cancers. Cox regression analysis and Gene Set Enrichment Analysis (GSEA) of a gene expression dataset from primary breast tumours with well annotated clinical and survival information was used to identify genesets associated with outcome. A geneset representing fatty acid oxidation (FAO) was then examined in other datasets. A doxycycline-inducible breast cancer cell line model overexpressing the rate-limiting enzyme in FAO, carnitine palmitoyl transferase 1A (CPT1A) was generated and analysed to confirm the association between FAO and cancer-associated characteristics in vitro. We identified a gene expression signature composed of 19 genes associated with fatty acid oxidation (FAO) that was significantly associated with patient outcome. We validated this observation in eight independent breast cancer datasets, and also observed the FAO signature to be prognostic in other cancer types. Furthermore, the FAO signature expression was significantly downregulated in tumours, compared to normal tissues from a variety of anatomic origins. In breast cancer, the expression of CPT1A was higher in oestrogen receptor (ER)-positive, compared to ER-negative tumours and cell lines. Importantly, overexpression of CPT1A significantly decreased the proliferation and wound healing migration rates of MDA-MB231 breast cancer cells, compared to basal expression control. Our findings suggest that FAO is downregulated in multiple tumour types, and activation of this pathway may lower cancer cell proliferation, and is associated with improved outcomes in some cancers.