GAS5 Downregulation Promotes the Progression of Triple-Negative Breast Cancer by Regulating Tumor Cells-MDSCs Crosstalk

Background: Triple-negative breast cancer (TNBC) is exceptionally aggressive, with a high recurrence rate, resistance to chemotherapy, and a tendency to metastasize. The long non-coding RNA growth arrest-specific 5 (GAS5) is associated with TNBC progression; however, the specific mechanism still requires further exploration. Methods: Integrative bioinformatics analyses and qRT-PCR were used to investigate the significant downregulation of GAS5 in TNBC cells and tissues. The functional role and molecular mechanism of GAS5 in inhibiting the progression of TNBC and increasing sensitivity to chemotherapy were investigated using in vitro experiments, including qPCR, Western blot, CCK8 assay, Transwell, Chemotaxis assays, RNA immunoprecipitation, m6A-RNA immunoprecipitation, Chromatin immunoprecipitation, Flow cytometry, ELISA, and Luciferase reporter assays, and in vivo experiments using tumor xenografts. Results: GAS5 was significantly downregulated in TNBC cells and tissues, as well as in chemotherapy-resistant conditions. Functional assays revealed that overexpression of GAS5 attenuated the progression of TNBC and increased their sensitivity to docetaxel (DTX) both in vitro and in vivo. Furthermore, we confirmed that GAS5 recruited YTHDF2 to target MYBL2, which in turn downregulated the chemokine CCL2, which reduced the recruitment of myeloid-derived immunosuppressive cells (MDSCs). In addition, IL-6 from MDSCs downregulated GAS5 to promote TNBC growth and attenuate the sensitivity of TNBC to DTX through the STAT3/UPF1 axis, forming a feedback loop between tumor cells and MDSCs. Conclusions: These findings illustrated the significance of the GAS5-mediated mutual regulatory pathway between tumor cells and MDSCs in TNBC and provide new avenues for the development of targeted therapies in TNBC.