The unconventional secretion of proteins is generally caused by cellular stress. During the tumorigenesis, tumor cells experience high levels of stress, and the secretion of some theoretically intracellular proteins is activated. Once in the extracellular space, these proteins play different paracrine and autocrine roles and could represent a vulnerability of cancer. One of these proteins is the high mobility group A1 (HMGA1), which is frequently overexpressed in tumors and presents a low expression in normal adult tissues. We have recently described that HMGA1 establishes an autocrine loop in invasive triple-negative breast cancer (TNBC) cells. The secretion of HMGA1 and its binding to the receptor for advanced glycation end products (RAGE) mediates the migration, invasion, and metastasis of TNBC cells and predicts the onset of metastasis in these patients. In this review, we summarized different strategies to exploit the novel tumorigenic phenotype mediated by extracellular HMGA1. We envisioned future clinical applications where the association between its change in subcellular localization and breast cancer progression could be used to predict tumor aggressiveness and guide treatment decisions. Furthermore, we proposed that targeting extracellular HMGA1 as monotherapy using monoclonal antibodies, or in combination with chemotherapy and other targeted therapies, could bring new therapeutic options for TNBC patients.
Keywords: cancer secretome; high mobility group A1 (HMGA1); receptor for advanced glycation end products (RAGE); triple-negative breast cancer (TNBC); tumor biomarkers.