MUS81 inhibits cell proliferation and migration in breast cancer by promoting the expression of CDKN2A(p16(INK4a)).

MUS81 has been recognized as a significant tumor suppressor - essential for DNA damage repair and maintaining chromosomal stability. However, its biological function and expression profile in breast cancer (BC) remain unclear. In this investigation, we examined the relationship between MUS81 expression and the proliferative and migratory capacities of BC cells. MUS81 mRNA and protein levels were markedly lower in breast cancer tissues and cell lines than in adjacent normal tissues and non-tumorigenic MCF-10A cells. Functional assays revealed that MUS81 overexpression suppressed, while MUS81 silencing enhanced, BC cell proliferation and motility, as demonstrated by CCK-8, colony formation, wound-healing, and Transwell experiments. In vivo, MUS81 overexpression markedly reduced Ki-67 expression in xenograft tumors. Although MUS81 did not alter CDKN2A mRNA expression, immunohistochemistry and Western blot analyses showed that p16(INK4a) protein levels increased following MUS81 overexpression. Furthermore, the modulation of p16(INK4a) expression by MUS81 was abolished by pretreatment with cycloheximide or MG132, suggesting that MUS81 stabilizes p16(INK4a) by preventing proteasome-mediated degradation. Collectively, these findings indicate that MUS81 works as a tumor suppressor in BC by inhibiting proliferation and migration through post-translational stabilization of p16(INK4a).