Transcriptomic analysis of human primary breast cancer identifies fatty acid oxidation as a target for metformin

Abstract

BACKGROUND: Epidemiological studies suggest that metformin may reduce the incidence of cancer in patients with diabetes and multiple late phase clinical trials assessing the potential of repurposing this drug are underway. Transcriptomic profiling of tumour samples is an excellent tool to understand drug bioactivity, identify candidate biomarkers and assess for mechanisms of resistance to therapy. METHODS: Thirty-six patients with untreated primary breast cancer were recruited to a window study and transcriptomic profiling of tumour samples carried out before and after metformin treatment. RESULTS: Multiple genes that regulate fatty acid oxidation were upregulated at the transcriptomic level and there was a differential change in expression between two previously identified cohorts of patients with distinct metabolic responses. Increase in expression of a mitochondrial fatty oxidation gene composite signature correlated with change in a proliferation gene signature. In vitro assays showed that, in contrast to previous studies in models of normal cells, metformin reduces fatty acid oxidation with a subsequent accumulation of intracellular triglyceride, independent of AMPK activation. CONCLUSIONS: We propose that metformin at clinical doses targets fatty acid oxidation in cancer cells with implications for patient selection and drug combinations. CLINICAL TRIAL REGISTRATION: NCT01266486.

Metabolism and cancer: the future is now

“…Therefore, the inhibition of PKM2 causes calcium overload and cell death, rather than the expected metabolic catastrophe. In a different context, breast cancer, Lord and colleagues 14 elegantly showed that metformin, a drug commonly used in Type 2 diabetes but with promising yet unclear anticancer effects, acts as an inhibitor of fatty acid oxidation at clinical doses. This work, together with their previous finding that the mitochondrial response to metformin in primary breast cancer defines antitumour effect, 15 suggests that metabolic profiling can be used to predict the response to metformin, and more in general to anticancer drugs.…”

Metformin suppresses HIF‐1α expression in cancer‐associated fibroblasts to prevent tumor‐stromal cross talk in breast cancer

“…12 Met represses fatty acid oxidation independent of AMP kinase (AMPK) activation, which results in an accumulation of intracellular triglycerides in breast cancer cells. 13 Nonetheless, the anticancer mechanism of Met remains unclear. In the present study, we examined whether, in addition to cancer cells, Met can be used to target the breast cancer TME to render it inhospitable for cell growth and invasion.…”

Tumor Metabolic Reprogramming by Adipokines as a Critical Driver of Obesity-Associated Cancer Progression

“…However, since many metabolic pathways in cancer cells are far different from those in non-malignant cells, caution should be taken to extrapolate the linkage between modulation of tumor growth and FAO by adiponectin. In fact, metformin, a potent activator of AMPK and FAO under physiological conditions, was demonstrated to inhibit FAO in breast cancer cells [ 105 ]. In summary, although adiponectin possesses various effects on lipid metabolism, future investigations are required for unraveling the involvement of adiponectin-induced alterations in cancer-related lipid metabolism in tumor progression.…”

“…It has been suggested that AMPK activators, such as AICAR (5-aminoimidazole-4-carboxamide-1-β-d-ribofuranoside) and metformin, show metabolic effects similar to adiponectin under physiological conditions [ 168 , 169 , 170 ]. Furthermore, compelling evidence indicates that AMPK activators suppress tumor growth though inhibition of de novo lipogenesis [ 105 , 171 , 172 ]. Therefore, reactivation of AMPK may serve as a potential intervention to reverse promoting effects of obesity on cancer metabolism.…”