HMGA2 Supports Cancer Hallmarks in Triple-Negative Breast Cancer

SIMPLE SUMMARY: Triple-negative breast cancer grows and spreads faster compared to other types of invasive breast cancer and has limited treatment options and subsequently worse prognosis. High mobility group A 2 (HMGA2) protein is widely expressed in undifferentiated cells including cancer cells. HMGA2 is a DNA binding protein involved in DNA architecture and the functional regulation of DNA. It was reported that HMGA2 is aberrantly regulated malignant signaling in different types of cancers. In this study, we aim to reveal the role of HMGA2 in TNBC biology and demonstrate a link between HMGA2-mediated cancer phenotypes and the regulation of NF-kB/IL-6/STAT3 signaling. ABSTRACT: Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer that exhibits a high proliferation rate and early metastasis leading to a poor prognosis. HMGA2 is a DNA binding transcriptional regulator implicated in tumorigenesis. Here, we demonstrate that the HMGA2 promoter is demethylated in TNBC tumors, leading to increased expression of HMGA2 at both mRNA and protein levels. Importantly, high HMGA2 levels in TNBC tumors are correlated with poor prognosis. To detail the role of HMGA2 in TNBC development and progression, we studied its effect on core cancer phenotypes. Stable knockdown of HMGA2 in TNBC cells revealed that HMGA2 may support cell proliferation, cell migration and invasion. In addition, HMGA2 knockdown decreased cancer stem cell (CSC) features. Importantly, we found that silencing HMGA2 inhibited NF-kB signaling and lead to decreased expression of the downstream molecules IL-6 and IL-8 and reduced STAT3 pathway activation. Our results demonstrate that HMGA2 supports cancer hallmarks in TNBC and may represent a promising target for TNBC treatment.