Changes in insulin receptor signaling underlie neoadjuvant metformin administration in breast cancer: a prospective window of opportunity neoadjuvant studyReportar como inadecuado

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Breast Cancer Research

, 17:32

First Online: 03 March 2015Received: 19 November 2014Accepted: 19 February 2015DOI: 10.1186-s13058-015-0540-0

Cite this article as: Dowling, R.J., Niraula, S., Chang, M.C. et al. Breast Cancer Res 2015 17: 32. doi:10.1186-s13058-015-0540-0


IntroductionThe antidiabetic drug metformin exhibits potential anticancer properties that are believed to involve both direct insulin-independent and indirect insulin-dependent actions. Direct effects are linked to activation of AMP-activated protein kinase AMPK and an inhibition of mammalian target of rapamycin mTOR signaling, and indirect effects are mediated by reductions in circulating insulin, leading to reduced insulin receptor IR-mediated signaling. However, the in vivo impact of metformin on cancer cell signaling and the factors governing sensitivity in patients remain unknown.

MethodsWe conducted a neoadjuvant, single-arm -window of opportunity- trial to examine the clinical and biological effects of metformin on patients with breast cancer. Women with untreated breast cancer who did not have diabetes were given 500 mg of metformin three times daily for ≥2 weeks after diagnostic biopsy until surgery. Fasting blood and tumor samples were collected at diagnosis and surgery. Blood glucose and insulin were assayed to assess the physiologic effects of metformin, and immunohistochemical analysis of tumors was used to characterize cellular markers before and after treatment.

ResultsLevels of IR expression decreased significantly in tumors P = 0.04, as did the phosphorylation status of protein kinase B PKB-Akt S473, extracellular signal-regulated kinase 1-2 ERK1-2, T202-Y204, AMPK T172 and acetyl coenzyme A carboxylase S79 P = 0.0001, P < 0.0001, P < 0.005 and P = 0.02, respectively. All tumors expressed organic cation transporter 1, with 90% 35 of 39 exhibiting an Allred score of 5 or higher.

ConclusionsReduced PKB-Akt and ERK1-2 phosphorylation, coupled with decreased insulin and IR levels, suggest insulin-dependent effects are important in the clinical setting. These results are consistent with beneficial anticancer effects of metformin and highlight key factors involved in sensitivity, which could be used to identify patients with breast cancer who may be responsive to metformin-based therapies.

Trial identifier: NCT00897884. Registered 8 May 2009.

AbbreviationsACCAcetyl coenzyme A carboxylase


AMPKAMP-activated protein kinase

BMIBody mass index


EGFEpidermal growth factor

EREstrogen receptor

ERKExtracellular signal-regulated kinase

FFPEFormalin-fixed, paraffin-embedded

Her2Human epidermal growth factor receptor 2

HOMAHomeostatic model assessment

IGFR-1Insulin-like growth factor 1 receptor


IQRInterquartile range

IRInsulin receptor

LKB1Liver kinase B1

MAPKMitogen-activated protein kinase

MEK1-2Mitogen-activated protein kinase kinase 1-2

mTORMammalian target of rapamycin

mTORC1Mammalian target of rapamycin complex 1

OCT1Organic cation transporter 1

PI3KPhosphatidylinositol 3-kinase

PKBProtein kinase B


Electronic supplementary materialThe online version of this article doi:10.1186-s13058-015-0540-0 contains supplementary material, which is available to authorized users.

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Autor: Ryan JO Dowling - Saroj Niraula - Martin C Chang - Susan J Done - Marguerite Ennis - David R McCready - Wey L Leong -


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