Reduced MUC4 Expression is a Late Event.in Breast Carcinogenesis and is Correlated With Increased Infiltration of Immune Cells as Well as Promoter Hypermethylation in Invasive Breast Carcinoma

摘要

Altered expression of MUC4 is associated with tumor progression and immune surveillance, but the potential involvement of MUC4 in breast carcinogenesis has not been rigorously assessed. Immunohistochemical staining with anti-MUC4 antibody was performed in a total of 324 patients with 26 normal breasts, 25 usual ductal hyperplasia, 76 ductal carcinoma in situ, and 198 invasive breast carcinoma (IBC) using tissue micro-array. Immunohistochemical staining for CD8, CD57, and CD1a and methylation-specific polymerase chain reaction were also performed in IBC. Reduced MUC4 expression in IBC was significantly higher than in usual ductal hyperplasia and ductal carcinoma in situ (P < 0.001 and P < 0.01, respectively). Reduced MUC4 expression in IBC was significantly correlated with promoter hypermethylation (P < 0.05). No association between MUC4 expression and patient outcomes was identified. Intratumoral CD8~+ T cells and stromal CD57~+ natural killer cells were significantly increased in the reduced MUC4 expression group compared with those in the normal expression group (P < 0.01 and P < 0.05, respectively). Our results suggest that tumor progression in breast epithelium is accompanied by reduced MUC4 protein expression. Reduced MUC4 expression correlates with increased tumor-infiltrating CD8~+ T and NK cells as well as promoter hypermethylation in IBC.