Abstract
Abstract Hypermethylation of CpG islands in the promoter region of tumor suppressor genes is a common event in cancer, and is an important mechanism in inactivating tumor suppressor gene function in breast cancer. Computational searches of existing large databases for genes underexpressed in multiple cancers, combined with CpG island analysis of those genes, identified a novel potential methylation marker gene in breast cancer called MAL (Maturation-Associated protein for T-Lymphocyte). MAL encodes a 17kD protein that is found in mature T-cells and participates in T-cell differentiation and T-cell receptor signaling. Recent studies have reported gene promoter hypermethylation of MAL in breast tumors and breast cancer cell lines. Furthermore, MAL inactivation has been shown to be predictive of benefit from adjuvant chemotherapy. We proposed that alteration of MAL expression has functional implications in breast cancer. In addition, we proposed that MAL has the potential to serve as a 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 (11/22; 50%) and in distant metastasis (16/32; 50%), but not in normal breast tissues or human mammary epithelial cells (HMECs). The high frequency of MAL methylation was common to all of the subtypes of breast cancer cells tested (Basal A, Basal B, and Luminal). Q-RT-PCR analysis of MAL expression and QM-MSP analysis of MAL methylation showed that 71% (20/28) of breast cancer cell lines show an inverse correlation between methylation and mRNA expression. This suggests that epigenetic alteration is the major mechanism of silencing since pharmacologic intervention with demethylating agents and histone deacetylase inhibitors resulted in re-expression of MAL in the breast cancer cell lines tested. MAL methylation is being assessed in a panel of 150 primary tumor samples with corresponding clinical data such as histological subtype, tumor grade and tumor specific survival. This will allow for correlations to be made between MAL methylation status and survival data etc. to see if MAL can serve as a predictive marker for breast cancer. This analysis will be useful in further validating MAL as a DNA methylation marker for breast cancer detection in tissue samples. 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 could provide a valuable early detection tool for breast cancer. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P3-04-06.
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