Changes in XXXX signaling underlie neoadjuvant metformin administration in @entity0 : a prospective window of opportunity neoadjuvant study.

@entity1 @entity3871 @entity0 @entity6 @entity5 @entity3962 @entity8277 @entity3470 @entity33725 @entity1366
INTRODUCTION: The 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 @entity33725 ( @entity33725 ) and an inhibition of @entity1 target of rapamycin @entity3470 signaling, and indirect effects are mediated by reductions in circulating insulin, leading to reduced @entity8277 ( @entity8277 )-mediated signaling. However, the in vivo impact of metformin on cancer cell signaling and the factors governing sensitivity in @entity1 remain unknown. METHODS: We conducted a neoadjuvant, single-arm, "window of opportunity" trial to examine the clinical and biological effects of metformin on @entity1 with @entity0 . @entity1 with untreated @entity0 who did not have @entity6 were given 500  mg of metformin three times daily for >= 2  weeks after diagnostic biopsy until surgery. Fasting @entity5 samples were collected at diagnosis and surgery. Blood glucose and insulin were assayed to assess the physiologic effects of metformin, and immunohistochemical analysis of @entity5 was used to characterize cellular markers before and after treatment. RESULTS: Levels of @entity8277 expression decreased significantly in @entity5 (P   =   0.04), as did the phosphorylation status of protein kinase B (PKB)/Akt (S473), @entity3962 ( @entity1366 , T202/Y204), @entity33725 (T172) and acetyl coenzyme A carboxylase (S79) (P   =   0.0001, P   <   0.0001, P   <   0.005 and P   =   0.02, respectively). All @entity5 expressed @entity3871 , with 90% (35 of 39) exhibiting an Allred score of 5 or higher. CONCLUSIONS: Reduced PKB/Akt and @entity1366 phosphorylation, coupled with decreased insulin and @entity8277 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 @entity1 with @entity0 who may be responsive to metformin-based therapies. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00897884. Registered 8 May 2009.
