PVT1 acts as a molecular scaffold to mediate PPARγ transcription and promote macrophage reprogramming in triple-negative breast cancer

Abstract Objective The long non-coding RNA (lncRNA) PVT1 plays a significant role in regulating the development and progression of various cancers. However, its clinical relevance in triple-negative breast cancer (TNBC) and its immunoregulatory mechanisms in TNBC remain largely unexplored. Methods An orthotopic TNBC mouse model was established, and single-cell RNA sequencing was performed on tumor tissues to examine macrophage populations. Bulk RNA sequencing, differential expression analysis, and Weighted Gene Co-expression Network Analysis were integrated to identify key factors of interest. Experiments using the co-culture si-PVT1-transduced oe-PPARγ TNBC cells with macrophages were conducted to observe their effects on TNBC cell growth and on M1/M2 marker expression both in vivo and in vitro. Additionally, the interactions of PVT1, NOP56, and E2F1 and their influence on PPARγ transcription were analyzed using RNA/DNA immunoprecipitation, ChIP-qPCR, and luciferase reporter assays. Results Macrophage reprogramming occurred in the TNBC tissues of mice, characterized by a significant accumulation of M2-type macrophages in tumor tissues. Both PVT1 and PPARγ play pivotal roles in this reprogramming. PVT1 knockdown (KD) suppressed the expression of PPARγ and M2 macrophage markers, while oe-PPARγ partially restored M2 marker expression. In vitro, PVT1 enhances TNBC cell proliferation, invasion, and metastasis through PPARγ. Similarly, in vivo, PVT1 promotes TNBC tumor growth and M2 marker expression via PPARγ. Mechanistically, PVT1 functions as a scaffold to recruit NOP56 and E2F1, forming a PVT1–NOP56–E2F1 complex that facilitates the transcriptional upregulation of PPARγ. Conclusion LncRNA PVT1 significantly affects macrophage polarization and TNBC progression by regulating PPARγ transcription. These findings suggest novel molecular targets for TNBC therapy development.