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

IntroductionThe anti-diabetic drug metformin exhibits potential anti-cancer properties, which are believed to involve both direct (insulin-independent) and indirect (insulin-dependent) actions. Direct effects are linked to activation of adenosine monophosphate (AMP)-activated protein kinase (AMPK) and an inhibition of mammalian target of rapamycin (mTOR) signaling, while 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. Methods: Therefore, we conducted a neoadjuvant, single arm, “window of opportunity” trial examining the clinical and biological effects of metformin on breast cancer patients. Non-diabetic women with untreated breast cancer were given 500 mg of metformin three times a day for ≥2 weeks post diagnostic biopsy until surgery. Fasting blood and tumour samples were collected at diagnosis and surgery. Blood glucose and insulin were assayed to assess the physiologic effects of metformin, while immunohistochemical analysis of tumours was used to characterize cellular markers before and after treatment. Results: Levels of IR expression decreased significantly in tumours (P = 0.04) as did the phosphorylation status of protein kinase B (PKB)/Akt (S473), extracellular signal-regulated kinase (ERK1/2, T202/Y204), AMPK (T172), and acetyl coA carboxylase (...
Source: Breast Cancer Research - Category: Cancer & Oncology Authors: Source Type: research