Integrated Pharmacodynamic Analysis Identifies Two Metabolic Adaption Pathways to Metformin in Breast Cancer.
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Date
2018-11-06ICR Author
Author
Lord, SR
Cheng, W-C
Liu, D
Gaude, E
Haider, S
Metcalf, T
Patel, N
Teoh, EJ
Gleeson, F
Bradley, K
Wigfield, S
Zois, C
McGowan, DR
Ah-See, M-L
Thompson, AM
Sharma, A
Bidaut, L
Pollak, M
Roy, PG
Karpe, F
James, T
English, R
Adams, RF
Campo, L
Ayers, L
Snell, C
Roxanis, I
Frezza, C
Fenwick, JD
Buffa, FM
Harris, AL
Type
Journal Article
Metadata
Show full item recordAbstract
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.
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Subject
Mitochondria
Humans
Breast Neoplasms
Metformin
Glucose
Antineoplastic Agents
Hypoglycemic Agents
Gene Expression Regulation, Neoplastic
Adult
Aged
Middle Aged
Female
Metabolic Networks and Pathways
Transcriptome
Positron Emission Tomography Computed Tomography
Language
eng
Date accepted
2018-08-24
Citation
Cell metabolism, 2018, 28 (5), pp. 679 - 688.e4
Publisher
CELL PRESS