Takayuki Iwamoto    Department   Kawasaki Medical School  Kawasaki Medical School, Department of Breast and Thyroid Surgery,    Position   Assistant Professor
Article types	原著
Language	English
Peer review	Peer reviewed
Title	Evidence for biological effects of metformin in operable breast cancer: a pre-operative, window-of-opportunity, randomized trial.
Journal	Formal name：Breast cancer research and treatment Abbreviation：Breast Cancer Res Treat ISSN code：15737217/01676806
Domestic / Foregin	Foregin
Volume, Issue, Page	128(3),pp.783-94
International coauthorship	International coauthorship
Author and coauthor	Sirwan Hadad, Takayuki Iwamoto, Lee Jordan, Colin Purdie, Susan Bray, Lee Baker, Gera Jellema, Steve Deharo, D Grahame Hardie, Lajos Pusztai, Stacy Moulder-Thompson, John A Dewar, Alastair M Thompson
Authorship	2nd author
Publication date	2011/08
Summary	Metformin may reduce the incidence of breast cancer and enhance response to neoadjuvant chemotherapy in diabetic women. This trial examined the effects of metformin on Ki67 and gene expression in primary breast cancer. Non-diabetic women with operable invasive breast cancer received pre-operative metformin. A pilot cohort of eight patients had core biopsy of the cancer at presentation, a week later (without treatment; internal control), then following metformin 500-mg o.d. for 1 week increased to 1-g b.d. for a further week continued to surgery. A further 47 patients had core biopsy at diagnosis were randomized to metformin (the same dose regimen) or no drug, and 2 weeks later had core biopsy at surgery. Ki67 immunohistochemistry, transcriptome analysis on formalin-fixed paraffin-embedded cores and serum insulin determination were performed blinded to treatment. Seven patients (7/32, 21.9%) receiving metformin withdrew because of gastrointestinal upset. The mean percentage of cells staining for Ki67 fell significantly following metformin treatment in both the pilot cohort (P = 0.041, paired t-test) and in the metformin arm (P = 0.027, Wilcoxon rank test) but was unchanged in the internal control or metformin control arms. Messenger RNA expression was significantly downregulated by metformin for PDE3B (phosphodiesterase 3B, cGMP-inhibited; a critical regulator of cAMP levels that affect activation of AMP-activated protein kinase, AMPK), confirmed by immunohistochemistry, SSR3, TP53 and CCDC14. By ingenuity pathway analysis, the tumour necrosis factor receptor 1 (TNFR1) signaling pathway was most affected by metformin: TGFB and MEKK were upregulated and cdc42 downregulated; mTOR and AMPK pathways were also affected. Gene set analysis additionally revealed that p53, BRCA1 and cell cycle pathways also had reduced expression following metformin. Mean serum insulin remained stable in patients receiving metformin but rose in control patients. This trial presents biomarker
DOI	10.1007/s10549-011-1612-1
PMID	21655990