Elevated HMGA2 expression is associated with cancer aggressiveness and predicts poor outcome in breast cancer

• HMGA2 expression positively correlates with histological grade of breast cancer.
• HMGA2 acts as an independent adverse predictor for breast cancer patients.
• GSEA indicates that HMGA2 is associated with metaplastic and mesenchymal phenotype.
• HMGA2 enhances the migration and invasion of BC cells through inducing EMT.
• HMGA2 protects BC cells against doxorubicin by stimulating P53 phosphorylation.

High mobility group AT-hook 2 (HMGA2) is involved in a wide spectrum of biological processes and is upregulated in several tumors. Here, we collected 273 breast cancer (BC) specimens as a training set and 310 specimens as a validation set to examine the expression of HMGA2 by immunohistochemical staining. It was found that HMGA2 expression was significantly positively correlated with advanced tumor grade and poor survival. Subgroup analysis indicated that high level of HMGA2 was significantly correlated with poor prognosis, especially in the subgroups of stage II–III, low pathological grade and non-triple negative breast cancer cases. Gene set enrichment analysis (GSEA) demonstrated a significant positive correlation between HMGA2 level and the gene expression signature of metaplastic and mesenchymal phenotype. Importantly, we also observed that ectopic expression of HMGA2 promoted the migration and invasion of breast cancer cells, and protected cancer cells against genotoxic stress from agents stimulating P53 (Ser15) phosphorylation. As a conclusion, expression of HMGA2 might indicate more advanced malignancy of breast cancer. Thus we believe HMGA2 could serve as a biomarker of poor prognosis and a novel target in treating BC tumors.