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.
Subject(s)
Breast Neoplasms/drug therapy , Fatty Acids/metabolism , Metformin/pharmacology , Protein Kinases/genetics , AMP-Activated Protein Kinase Kinases , Animals , Breast Neoplasms/genetics , Breast Neoplasms/metabolism , Breast Neoplasms/pathology , Cell Proliferation/drug effects , Diabetes Mellitus/drug therapy , Diabetes Mellitus/genetics , Diabetes Mellitus/metabolism , Female , Gene Expression Profiling/methods , Gene Expression Regulation, Neoplastic/drug effects , Heterografts , Humans , Lipid Metabolism/drug effects , Lipid Peroxidation/drug effects , Mice , Mitochondria/drug effects , Oxidation-Reduction/drug effects , Transcriptome/drug effectsABSTRACT
Late-phase clinical trials investigating metformin as a cancer therapy are underway. However, there remains controversy as to the mode of action of metformin in tumors at clinical doses. We conducted a clinical study integrating measurement of markers of systemic metabolism, dynamic FDG-PET-CT, transcriptomics, and metabolomics at paired time points to profile the bioactivity of metformin in primary breast cancer. We show metformin reduces the levels of mitochondrial metabolites, activates multiple mitochondrial metabolic pathways, and increases 18-FDG flux in tumors. Two tumor groups are identified with distinct metabolic responses, an OXPHOS transcriptional response (OTR) group for which there is an increase in OXPHOS gene transcription and an FDG response group with increased 18-FDG uptake. Increase in proliferation, as measured by a validated proliferation signature, suggested that patients in the OTR group were resistant to metformin treatment. We conclude that mitochondrial response to metformin in primary breast cancer may define anti-tumor effect.
Subject(s)
Antineoplastic Agents/pharmacology , Breast Neoplasms/drug therapy , Hypoglycemic Agents/pharmacology , Metabolic Networks and Pathways/drug effects , Metformin/pharmacology , Adult , Aged , Antineoplastic Agents/therapeutic use , Breast Neoplasms/genetics , Breast Neoplasms/metabolism , Female , Gene Expression Regulation, Neoplastic/drug effects , Glucose/analogs & derivatives , Glucose/metabolism , Humans , Hypoglycemic Agents/therapeutic use , Metformin/therapeutic use , Middle Aged , Mitochondria/drug effects , Mitochondria/genetics , Mitochondria/metabolism , Positron Emission Tomography Computed Tomography , Transcriptome/drug effectsABSTRACT
Carcinoid tumors are known to metastasize to the breast, but their appearance can mimic a primary breast carcinoma, making biopsy essential in order to give the correct preoperative diagnosis. It has been suggested that core biopsy might precipitate a carcinoid crisis and should be avoided. We describe a case of screen-detected carcinoid tumor metastasis in the breast safely diagnosed by core biopsy and present the imaging findings, including magnetic resonance imaging and elastography. This case illustrates the importance of preoperative histologic diagnosis in enabling the appropriate surgical or medical management of these patients. Review of the literature also supports the policy that biopsy of nonhormonally active tumors may be safely performed.