Inactivation of the MAL gene in breast cancer is a common event that predicts benefit from adjuvant chemotherapy.
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.
Horne
Hisani N
HN
Department of Pathology, Duke University Medical Center, Durham, NC 27710, USA. hnh4@duke.edu
Lee
Paula S
PS
Murphy
Susan K
SK
Alonso
Miguel A
MA
Olson
John A
JA
Marks
Jeffrey R
JR
D001374:Azacitidine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D001483:Base Sequence; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology; D017024:Chemotherapy, Adjuvant; D018899:CpG Islands; D019175:DNA Methylation; D000077209:Decitabine; D044127:Epigenesis, Genetic; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D020868:Gene Silencing; D006801:Humans; D007124:Immunoenzyme Techniques; D007834:Lasers; D021962:Membrane Microdomains / Q000378:metabolism; D026901:Membrane Transport Proteins / Q000235:genetics* / Q000378:metabolism; D008875:Middle Aged; D008969:Molecular Sequence Data; D009185:Myelin Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D062806:Myelin and Lymphocyte-Associated Proteolipid Proteins; D011379:Prognosis; D011401:Promoter Regions, Genetic / Q000235:genetics; D011510:Proteolipids / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015996:Survival Rate; D014945:Wound Healing
C569026:MAL protein, human; D026901:Membrane Transport Proteins; D009185:Myelin Proteins; D062806:Myelin and Lymphocyte-Associated Proteolipid Proteins; D011510:Proteolipids; D000077209:Decitabine; D001374:Azacitidine