WDR82 suppresses breast cancer progression by inhibiting ERK-driven chemokine expression and neutrophil infiltration

The immunosuppressive tumor microenvironment (TME) is a critical barrier to effective cancer immunotherapy, particularly in breast cancer. Current therapeutic strategies often fall short due to complex interactions between tumor-intrinsic factors and immune cells, leading to cancer immunoevasion. Understanding novel molecular regulators that orchestrate this immunosuppression is essential. WDR82, a WD-40 protein, has context-dependent roles in cancer, but its specific function in breast cancer and its impact on the TME remained undefined, representing a significant knowledge gap this study addresses.

Researchers investigated WDR82's role in breast cancer progression using both in vitro cell proliferation assays and in vivo tumor growth models in immunocompetent hosts. They analyzed WDR82 expression in human breast cancer tissues and correlated it with patient prognosis. To confirm dependency on immune cells, neutrophil depletion experiments were conducted in tumor-bearing mice. Mechanistically, they performed binding assays to identify WDR82's interaction partners, focusing on the MEK-ERK pathway. Finally, they delivered WDR82-expressing adenovirus intratumorally to evaluate its therapeutic potential on neutrophil accumulation, T cell exhaustion, and tumor progression.

WDR82 expression was consistently downregulated in human breast cancer tissues and correlated with poor prognosis. While WDR82 promoted tumor cell proliferation in vitro, its in vivo effect was strikingly different: it suppressed tumor growth exclusively in immunocompetent hosts. This tumor-suppressive effect was abolished by neutrophil depletion, confirming a functional dependency on this immune cell axis. Mechanistically, WDR82 directly bound MEK1/2, leading to the disassembly of c-RAF-MEK binding and subsequent inactivation of ERK signaling. > Wdr82 deletion restored ERK-dependent tumor cell CXCL2 and CXCL7 production, which in turn promoted CXCR2-mediated neutrophil recruitment within the TME. Importantly, intratumoral delivery of WDR82-expressing adenovirus reversed neutrophil accumulation and T cell exhaustion, effectively suppressing tumor progression.