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.
Highlights
Breast cancer, a major health concern worldwide [1], exhibits disparate clinical behaviors and patient outcomes [2]
A previous methylome study on breast cancer tissues detected inverse correlation between RECK CpG methylation and relapse-free survival. We focused on another region of the RECK CpG island and found an inverse correlation between its methylation and RECK-inducibility by an histone deacetylases (HDACs) inhibitor, MS275, among a panel of breast cancer cell lines (n=15)
RECK expression is low in cell lines positive for RIM (Figure 1D), suggesting the involvement of RIM in RECK silencing. These data suggest the value of these cell lines in studying how RIM affects RECK expression and the properties of breast cancer cells
Summary
A major health concern worldwide [1], exhibits disparate clinical behaviors and patient outcomes [2]. Ductal carcinoma in situ (DCIS) is a non-invasive breast lesion that accounts for 10-25% of all breast neoplasms; DCIS is not life-threatening but a risk factor for, and potential precursor of, invasive cancers. The most common histological type of breast cancers, accounting for ~80% of the cases, is invasive ductal carcinoma (IDC). A large fraction (70–75%) of IDCs are positive for ER and classified as luminal cancers. Besides luminal cancers, are HER2-enriched and triple-negative (ER-/PR-/HER2-) [2]. Breast cancer classification based on gene expression profiles www.impactjournals.com/oncotarget has been proposed [3]. Such molecular classifications of cancers are of great clinical importance, since they may provide molecular bases for predicting the tumors’ prognoses and/or responses to therapy [2]
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