Aberrant DNA methylation of integrin α4 in human breast cancer

Integrins are cell surface receptors that mediate cell-cell/extracellular interactions and have shown an association with metastasis or transformation in several cancers. However, the correlation between the clinicopathological status of breast cancer and the altered integrin alpha 4 status is not clear. In this study, we investigated DNA methylation of integrin alpha 4 in breast cancer. We retrieved 351 cases of surgically resected breast cancer (290 invasive carcinoma and 61 intraductal carcinoma). Methylation-specific polymerase chain reaction was performed to determine integrin alpha 4 methylation status. Integrin alpha 4 methylation was frequently observed in breast cancer specimens (145/351 cases, 41.3 %). In addition, DNA methylation of integrin alpha 4 showed statistical correlation with HER2 positivity and higher histologic grade (p = 0.001, 0.008 in ductal carcinoma in situ and 0.003 in invasive ductal carcinoma). However, other clinicopathological data such as estrogen receptor, progesterone receptor, metastasis, and TNM status showed no statistical correlation. Moreover, we found that the downregulated expression of integrin alpha 4 in a heavily methylated breast cancer cell line (ZR-75) was restored by treatment with 5-aza-2'deoxycytidine, a DNA methyltransferase inhibitor, implying transcriptional silencing by DNA methylation. We observed that integrin alpha 4 methylation is associated with the histologic grade of tumors and lymph node metastasis. Also, this data supports a previous study that suggested integrin alpha 4 and HER2 are involved in the same signaling pathway. DNA methylation of integrin alpha 4 may be a poor prognostic factor which affects undifferentiated histologic change of breast cancer.