SOX13-mediated transcription of LRP11 enhances malignant properties of tumor cells and CD8+ T cell inactivation in breast cancer through the β-catenin/PD-L1 axis

Abstract

Background

High expression of low-density lipoprotein receptor related protein 11 (LRP11) has been associated with unfavorable prognosis of breast cancer (BC). This study explores the exact roles of LRP11 in BC progression and investigates the associated mechanism.

Methods

LRP11 expression in BC tissues and cells was determined by immunohistochemistry or RT-qPCR. LRP11 upregulation was induced in two human BC cell lines to investigate its impact on cell proliferation, migration, and invasion. Its regulation on immune activity was assessed by detecting PD-L1 protein levels and generating a co-culture system of cancer cells and CD8⁺ T cells. Mouse allograft tumor models were generated to analyze the function of LRP11 in tumorigenesis and immune activity in vivo. Gain-of-function assays of SRY-box transcription factor 13 (SOX13) were performed to investigate its function in development and immunosuppression of BC.

Results

LRP11 was found to be highly expressed in BC tissues and cells, presenting an association with unfavorable prognosis of patients. Artificial upregulation of LRP11 in BC cells triggered malignant properties of cells, enhancing β-catenin-mediated transcriptional activation of PD-L1, thus decreasing immune activity of the co-cultured CD8⁺ T cells. Consistently, LRP11 upregulation in mouse 4 T1 cells and promoted tumorigenesis and immune evasion in mice. SOX13 was found to bind the LRP11 promoter for transcriptional activation. Upregulation of SOX13 similarly promoted growth of BC cells and immunosuppression, with its oncogenic effects blocked by the additional LRP11 knockdown.

Conclusion

This study demonstrates that SOX13 is responsible for LRP11 transcription activation, leading to increased malignant phenotype of BC cells and diminished activity CD8⁺ T cells. This evidence highlights SOX13 and LRP11 as promising novel therapeutic targets to reduce malignant phenotype of BC cells and overcome immunosuppression.