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ABSTRACTDespite improved therapeutic strategies for early-stage breast cancer, the most common cancer type in women, relapse remains common and the underlying mechanisms for this progression remain poorly understood. To gain more insight, we studied the DNA-binding protein HMGA2 in breast cancer development and stemness. We demonstrated that HMGA2 is overexpressed in breast cancer tissues at the mRNA and protein levels (P value <0.0001). HMGA2 knockdown and overexpression in breast cancer cells revealed that HMGA2 promotes cell proliferation and protects against apoptosis via the intrinsic pathway. HMGA2 knockdown also causes cell cycle arrest in G2/M phase. In addition, we found that HMGA2 increases breast cancer cell migration and invasion (P value <0.001) and promotes the acquisition of cancer stem cell features, both in vitro, in colony formation (P value <0.01) and spheroid assays, and in breast cancer tissues. Overexpression of HMGA2 in breast cancer spurs the acquisition of several hallmarks of cancer, including increased cell proliferation, migration, invasion and stemness, and decreased apoptosis. Thus, targeting HMGA2 could represent an effective strategy to block breast cancer progression.