Pattern of RECK CpG methylation as a potential marker for predicting breast cancer prognosis and drug-sensitivity

Abstract

The membrane-anchored glycoprotein RECK negatively regulates multiple metalloproteinases and is frequently downregulated in tumors. Forced RECK expression in cancer cells results in suppression of tumor angiogenesis, invasion, and metastasis in xenograft models. A previous methylome study on breast cancer tissues detected inverse correlation between RECK CpG methylation (in an intron-1 region) and relapse-free survival. In this study, we focused on another region of the RECK CpG island (a promoter/exon-1 region) and found an inverse correlation between its methylation and RECK-inducibility by an HDAC inhibitor, MS275, among a panel of breast cancer cell lines (n=15). In clinical samples (n=62), RECK intron-1 methylation was prevalent among luminal breast cancers as reported previously (26 of 38 cases; 68%) and particularly enriched in tumors of the ER+PR- subclass (10 of 10 cases) and of higher histological grades (Grade 2 and 3; 28 of 43 cases; P=0.006). In about a half of these cases, promoter/exon-1 methylation was absent, and hence, RECK may be inducible by certain drugs such as MS275. Our results indicate the value of combined use of two RECK methylation markers for predicting prognosis and drug-sensitivity of breast cancers.

DNA methylation landscape of triple-negative ductal carcinoma in situ (DCIS) progressing to the invasive stage in canine breast cancer

“…RECK, a gene involved in suppressing cancer cell migration, invasion, and metastasis, negatively regulates matrix metalloproteinase 9 (MMP9) by directly inhibiting its enzymatic activity and abolishing MMP9 secretion 55 . In previous studies, regulation of RECK by DNA methylation has been described and proposed as a potential marker for predicting breast cancer www.nature.com/scientificreports www.nature.com/scientificreports/ prognosis 56 . Finally, mitochondrial single-stranded DNA binding protein (SSBP1) is a negative regulator of metastasis whose downregulation leads to reduced mitochondrial DNA copy number and consequent activation of TGFβ-induced EMT 57 .…”

Methylation degree of metalloproteinase inhibitor RECK gene: Links to RECK protein level and hepatocellular carcinoma in chronic HCV infection patients

“…The different patterns of DNA methylation and their values as potential biomarkers for diagnoses and prognoses in many cancer cells have been studied in pancreatic cancer, [16,17] peripheral T-cell lymphoma, [3] breast cancer, [18] and esophageal squamous cell carcinoma. [19] The hypermethylated pattern of RECK gene promoter is also reported in many cancers such as non-small-cell lung carcinoma, colorectal, pancreas, and stomach cancers as well as HCC, [2] concordant with results obtained in the current study.…”

Identification of RECK as an evolutionarily conserved tumor suppressor gene for zebrafish malignant peripheral nerve sheath tumors

“…Along the same direction, TSG restoration was also demonstrated as another way of targeted therapy based on the biology of TSGs [ 53 ]. In the case of the RECK gene, it is frequently reported to be silenced through promoter methylation in a variety of human cancers [ 54 – 59 ]. Thus, attempts were made to restore RECK expression using DNA methyltransferase (DNMT) inhibitor, 5-aza-2′deoxycytidine (5-aza-dC), in colon cancer and salivary adenoid cystic carcinoma [ 60 , 61 ].…”