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

• Published in: Breast cancer research : BCR 2015-03, Vol.17 (1), p.32-32, Article 32
• Main Authors: Dowling, Ryan J O, Niraula, Saroj, Chang, Martin C, Done, Susan J, Ennis, Marguerite, McCready, David R, Leong, Wey L, Escallon, Jaime M, Reedijk, Michael, Goodwin, Pamela J, Stambolic, Vuk
• Format: Article
• Language: English
• Subjects: Adult; Aged; Analysis; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Biomarkers - metabolism; Blood sugar; Breast cancer; Breast Neoplasms - drug therapy; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Cancer; Care and treatment; Diabetes therapy; Enzymes; Female; Genetic aspects; Health aspects; Humans; Insulin; Metformin - pharmacology; Metformin - therapeutic use; Middle Aged; Mitogen-Activated Protein Kinase 1 - metabolism; Mitogen-Activated Protein Kinase 3 - metabolism; Neoadjuvant Therapy; Neoplasm Grading; Neoplasm Staging; Oncology, Experimental; Phosphorylation; Protein kinases; Proto-Oncogene Proteins c-akt - metabolism; Receptor, Insulin - metabolism; Risk factors; Signal Transduction - drug effects; Type 2 diabetes
• ISSN: 1465-542X; 1465-5411; 1465-542X
• DOI: 10.1186/s13058-015-0540-0

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 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. We 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. Levels 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