Inactivation of the MAL Gene in Breast Cancer Is a Common Event That Predicts Benefit from Adjuvant Chemotherapy

Abstract

Dysregulation of MAL (myelin and lymphocyte protein) has been implicated in several malignancies including esophageal, ovarian, and cervical cancers. The MAL protein functions in apical transport in polarized epithelial cells; therefore, its disruption may lead to loss of organized polarity characteristic of most solid malignancies. Bisulfite sequencing of the MAL promoter CpG island revealed hypermethylation in breast cancer cell lines and 69% of primary tumors analyzed compared with normal breast epithelial cells. Differential methylation between normal and cancer DNA was confined to the proximal promoter region. In a subset of breast cancer cell lines including T47D and MCF7 cells, promoter methylation correlated with transcriptional silencing that was reversible with the methylation inhibitor 5-aza-2 ¶-deoxycytidine. In addition, expression of MAL reduced motility and resulted in a redistribution of lipid raft components in MCF10A cells. MAL protein expression measured by immunohistochemistry revealed no significant correlation with clinicopathologic features. However, in patients who did not receive adjuvant chemotherapy, reduced MAL expression was a significant predictive factor for disease-free survival. These data implicate MAL as a commonly altered gene in breast cancer with implications for response to chemotherapy.

MAL and TMEM220 are novel DNA methylation markers in human gastric cancer

“…These findings agree with predictions made in our previous study (Figure 2a). To date, several studies have reported MAL gene methylation and mRNA-expression patterns in various cancers such as oral, breast, colon, and GC (Lind et al, 2008, Pal et al, 2012, Horne et al, 2009, Buffart et al, 2008. Buffart et al found an association between mRNA-expression levels and the methylation status of the MAL promoter region (Buffart et al, 2008).…”

Differential promoter methylation of kinesin family member 1a in plasma is associated with breast cancer and DNA repair capacity

“…MAL encodes a trans-membrane protein involved in the sorting of proteins for signaling and transport, and therefore is expressed in most types of epithelial cells (22). Epigenetic regulation of MAL in BC has been described and associated with silencing of expression.…”

Suppression of MAL gene expression is associated with colorectal cancer metastasis

“…Loss of MAL leads to the loss of the polarized phenotype that frequently accompanies the neoplastic transformation process (14). Recent studies have suggested that downregulation of MAL has been associated with a variety of human epithelial malignancies, including esophageal (7), breast (8), ovarian (9) and cervical (15) cancers. For example, Mimori et al showed that overexpression of MAL in esophageal tumors exhibited decreased cellular motility, a G 1 /S transition block and increased levels of apoptosis via the Fas signaling pathway (7).…”

“…For example, Mimori et al (7) initially found that MAL was highly expressed in normal esophageal epithelia, but silenced in esophageal tumors. Later, inactivation of MAL was shown to be a common event in breast, head and neck, and gastric cancer (8)(9)(10)(11). However, the functional role and mechanistic action of MAL in CRC remains largely unknown.…”