Abstract 4916: MAL, a frequently methylated gene marker for early detection of breast cancer

Abstract

Abstract Hypermethylation of CpG islands in the promoter region of tumor suppressor genes is a common event in cancer, and often results in transcriptional silencing. Computational searches of existing large databases for genes underexpressed in multiple cancers, combined with CpG island analysis of those genes, identified a novel methylation marker gene in breast cancer called MAL (Maturation-Associated protein for T-Lymphocyte). MAL encodes a 17kD lipid raft protein that is found in mature T-cells and participates in T-cell differentiation and T-cell receptor signaling. Two previous studies have reported gene promoter hypermethylation of MAL in primary breast tumors and breast cancer cell lines. Furthermore, Horne et al found MAL inactivation is predictive of benefit from adjuvant chemotherapy. We propose that alteration of MAL expression is functionally important in breast cancer. In addition, we propose that MAL has the potential to serve as a serum methylation marker for early detection of breast cancer. MAL gene methylation as assessed in breast cancer cell lines and primary tumors by quantitative multiplex methylation specific PCR (QM-MSP) showed that it is frequently methylated in cell lines (40/48; 83%), in primary tumors (11/20; 55%) and in distant metastasis (18/35; 51%), but not in normal breast tissues. Hypermethylation of MAL resulted in its decreased expression in the majority of the samples tested. Treatment of breast cancer cell lines with demethylating agents and histone deacetylase inhibitors restored MAL expression, thus establishing epigenetic alterations as the major mechanism of silencing. The function of MAL is being deciphered at both the biological and biochemical level by performing overexpression and knockdown studies in breast cells using already constructed expression vectors. The characterization and validation of MAL, a lipid raft protein, as a potential DNA methylation marker in breast cancer, particularly in serum, could provide a valuable early detection and prediction tool for breast cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4916.