NR4A1 and neoplasm: This observational signal, backed by numerous preclinical studies showing metformin’s anti-tumor effects across subtypes, motivated the MA.32 trial—a phase III, randomized, double-blind, placebo-controlled study conducted from August 2010 to March 2013 in Canada, Switzerland, the US, and the UK; the study involved 3649 non-diabetic, high-risk operable breast cancer patients (stratified by hormone receptor status, HER2 status, BMI, and chemotherapy) that received either 850 mg metformin or placebo twice daily for five years.