Signal transducer and activator of transcription 3 (STAT3) is responsible for mediating\nthe transcriptional programs downstream of several cytokine, growth factor, and oncogenic stimuli.\nIts expression and activity are consistently linked to cellular transformation, as well as tumor initiation\nand progression. Due to this central role, STAT3 is widely considered a good target for anti-cancer\ntherapy; however, the success of these approaches has been, so far, very limited. Notably, on one side,\nSTAT3 is aberrantly active in many breast cancers, on the other, at the physiological level, it is the\nmain mediator of epithelial cell death during post-lactation mammary-gland involution, thus strongly\nsuggesting that its biological functions are highly context-specific. One of the most peculiar features\nof STAT3 is that it can act both in cell-autonomous and non-cell-autonomous manners, simultaneously\nmodulating the phenotypes of the tumor cells and their microenvironment. Here, we focus on the role\nof STAT3 in breast cancer progression, discussing the potential contrasting roles of STAT3 activation\nin the establishment of locally recurrent and distant metastatic disease. Based on the most recent\nliterature, depending on the tumor cell type, the local microenvironment status, and the stage of\nthe disease, either STAT3 activation or inactivation can support disease progression. Accordingly,\ncancer cells dynamically exploit STAT3 activity to carry out transcriptional programs somehow\ncontrasting and complementary, such as supporting survival and growth, dormancy and awakening,\nstem cell-like features, and inflammation, immune response, and immune evasion. As a consequence,\nto achieve clinical efficacy, the conception and testing of anti-STAT3 targeted therapies will need a very\ncareful evaluation of these opposing roles and of the most appropriate tumor context, disease stage\nand patient population to treat.
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