Identification of RPGRIP1L as an instability-maintaining gene to drive tumor growth and PD-L1 expression via Hedgehog signaling in breast cancer

Genomic instability is a hallmark of nearly all human cancers, yet the genetic regulators that govern this instability, their functional roles, and their therapeutic potential remain incompletely understood in breast cancer. In this study, we conducted a comprehensive analysis of the expression profiles of genomic instability-maintaining genes (GIMGs) in breast cancer and revealed that elevated expression of GIMGs was associated with adverse clinical outcomes and an altered tumor immune microenvironment. Through further analysis, we identified a core set of GIMGs and pinpointed RPGRIP1L as a critical driver of genomic instability in breast cancer. Notably, RPGRIP1L expression was significantly upregulated in breast cancer tissues and strongly correlated with poor patient prognosis. Functional studies demonstrated that RPGRIP1L knockdown reduced genomic instability in tumor cells, as evidenced by decreased Phosphorylated Histone H2AX (γH2AX) expression, and suppressed tumor growth in mouse models. Additionally, high RPGRIP1L expression was linked to elevated expression of immune checkpoint Programmed Death Ligand 1(PD-L1) in human breast cancer samples. Mechanistically, we found that RPGRIP1L promoted the activation of the Hedgehog signaling pathway, which in turn drived tumor proliferation and upregulated PD-L1 expression. Collectively, these findings highlight RPGRIP1L as a key genomic instability-maintaining gene in human breast cancer, offering critical insights into the molecular mechanisms underlying disease progression. Furthermore, targeting RPGRIP1L may represent a promising therapeutic strategy for breast cancer.