Association of Protein Expression and Methylation of DAPK1 with Clinicopathological Features in Invasive Ductal Carcinoma Patients from Kashmir

Abstract

Aims: Death-associated protein kinase-1 (DAPK1) is a pro-apoptotic Ser/Thr kinase that participates in cell apoptosis<br />and tumor suppression. DAPK1 is frequently lost in many different tumor types including breast cancer. The aim of<br />this study was to evaluate the promoter methylation status of DAPK1 and a possible correlation with the expression<br />of DAPK1 and standard clinicopathological features in invasive ductal breast carcinoma patients (IDC). Methods:<br />Methylation Specific PCR (MSP) was carried out to investigate the promoter methylation status of DAPK1 from 128<br />breast cancer patients. The effect of promoter methylation on protein expression was evaluated by immunohistochemistry<br />(n=128) and western blotting (n=56). Results: We found significant difference in DAPK1 promoter methylation<br />frequency among breast tumors when compared with the corresponding normal tissues. Hypermethylation of DAPK1<br />is significantly correlated with the loss of DAPK1 protein expression (P < .001, rs= -0.361). The loss of DAPK1 protein<br />was significantly associated with estrogen receptor (ER) negativity (p= 0.003), triple negative breast cancer (TNB)<br />(p= 0.024) and advanced tumor stages (P = 0.001). Moreover, age at diagnosis (p= 0.041), tumor stage (p= 0.034), ER<br />negativity (p= 0.004) and TNB cancers (p=0.003) correlated significantly with the hypermethylation of the DAPK1<br />promoter. Coclusion: This study indicates that DAPK1 is methylated in IDC and promoter hypermethylation could be<br />attributed to silencing of DAPK1 gene expression in breast cancer. Thus, we consider DAPK1 inactivation by promoter<br />hypermethylation likely plays a role in the development and progression of breast cancer.