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Methylation‐dependent silencing of CST6 occurs in primary human breast tumors and lymph node metastases
Author(s) -
Rivenbark Ashley G,
Livasy Chad A,
Boyd Courtney E,
Keppler Daniel,
Coleman William B
Publication year - 2007
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.21.6.a756-b
Subject(s) - dna methylation , cancer research , gene silencing , breast cancer , methylation , biology , epigenetics , lymph node , carcinogenesis , cpg site , cancer , oncology , pathology , medicine , immunology , gene expression , gene , genetics
Cystatin M (CST6) is a breast cancer tumor suppressor that is expressed in normal and premalignant breast epithelium, but not in metastatic breast cancer cell lines. CST6 is silenced in breast cancer cells as a consequence of hypermethylation of the CpG island that encompasses its proximal promoter region and exon 1. Primary breast tumors (n=5) and lymph node metastases (n=12) expressed significantly lower levels of Cystain M protein compared to normal breast tissue. Bisulfite sequencing demonstrated extensive CST6 hypermethylation in 6/17 (35%) and moderate CpG methylation in 4/17 (24%) neoplastic lesions. The extent of CST6 methylation correlates with loss of protein expression in the majority of primary tumors and lymph node metastases. Furthermore, lymph node metastases exhibited diminished levels of Cystatin M protein compared to matched primary tumors, accompanied by increased levels of CST6 promoter hypermethylation. These results suggest that methylation‐dependent epigenetic silencing of CST6 represents an important mechanism for loss of CST6 during breast tumorigenesis. Loss of CST6 expression is associated with the invasive/metastatic potential of breast cancer cells, and methylation‐dependent CST6 gene silencing may represent an informative marker for invasive cancer cells that predicts metastatic potential. Support: NIH CA78343, NIH CA91785, Komen Foundation BCTR0100575.