Abstract
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 registrationClinicalTrials.gov identifier: NCT00897884. Registered 8 May 2009.Electronic supplementary materialThe online version of this article (doi:10.1186/s13058-015-0540-0) contains supplementary material, which is available to authorized users.
Highlights
The antidiabetic drug metformin exhibits potential anticancer properties that are believed to involve both direct and indirect actions
Metformin had a significant impact on signaling in tumor cells, as expression of the insulin receptor (IR) and phosphorylation of protein kinase B (PKB)/Akt and ERK1/2 decreased upon treatment
The results reported here demonstrate that short-term administration of metformin in patients with breast cancer who do not have diabetes induces tumor-specific changes in IR expression and cell signaling, which are consistent with beneficial anticancer effects of the drug
Summary
The antidiabetic drug metformin exhibits potential anticancer properties that are believed to involve both direct (insulin-independent) and indirect (insulin-dependent) actions. Metformin use has been associated with increased pathologic complete response rates to neoadjuvant therapy [4]. These retrospective studies are subject to selection and time-related biases, highlighting the need for well-designed prospective clinical trials [5]. The indirect, insulin-dependent effects of metformin are associated with reductions in circulating insulin levels in patients [9,10] and are likely mediated by inhibition of gluconeogenesis in the liver and increased glucose uptake in muscle [11,12]. Metformin may diminish the stimulatory effects of insulin on breast cancer
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