Loss, mutation and deregulation of L3MBTL4 in breast cancers

Abstract

BackgroundMany alterations are involved in mammary oncogenesis, including amplifications of oncogenes and losses of tumor suppressor genes (TSG). Losses may affect almost all chromosome arms and many TSGs remain to be identified.ResultsWe studied 307 primary breast tumors and 47 breast cancer cell lines by high resolution array comparative genomic hybridization (aCGH). We identified a region on 18p11.31 lost in about 20% of the tumors and 40% of the cell lines. The minimal common region of loss (Chr18:6,366,938-6,375,929 bp) targeted the L3MBTL4 gene. This gene was also targeted by breakage in one tumor and in two cell lines. We studied the exon sequence of L3MBTL4 in 180 primary tumor samples and 47 cell lines and found six missense and one nonsense heterozygous mutations. Compared with normal breast tissue, L3MBTL4 mRNA expression was downregulated in 73% of the tumors notably in luminal, ERBB2 and normal-like subtypes. Losses of the 18p11 region were associated with low L3MBTL4 expression level. Integrated analysis combining genome and gene expression profiles of the same tumors pointed to 14 other potential 18p TSG candidates. Downregulated expression of ZFP161, PPP4R1 and YES1 was correlated with luminal B molecular subtype. Low ZFP161 gene expression was associated with adverse clinical outcome.ConclusionWe have identified L3MBTL4 as a potential TSG of chromosome arm 18p. The gene is targeted by deletion, breakage and mutations and its mRNA is downregulated in breast tumors. Additional 18p TSG candidates might explain the aggressive phenotype associated with the loss of 18p in breast tumors.

Loss of protein tyrosine phosphatase, non-receptor type 2 is associated with activation of AKT and tamoxifen resistance in breast cancer

“…identified PTPN2 as one candidate tumour suppressor gene in this region and showed a correlation between PTPN2 gene loss and low mRNA expression levels [8]. In the present study, we confirm the correlation between PTPN2 gene deletion and low mRNA expression levels in a breast cancer material.…”

“…Loss of 18p in breast tumours has previously been related to poor outcome [7] and an association between 18p deletion and decreased levels of PTPN2 mRNA has been reported [8].It may be hypothesised that loss of 18p in breast cancer could lead to decreased levels of PTPN2 and be one previously unexplored mechanism behind PI3K/AKT pathway overstimulation in breast tumours.…”

Chromatin regulation: How complex does it get?

“…28 In accordance with the l(3)mbt phenotype in Drosophila several human MBT domain proteins (L3MBTL1, L3MBTL2, L3MBTL3, L3MBTL4, and SCML2) have been implicated in tumorigenesis. [28][29][30][31][32][33] In addition to MBT modules, these proteins often contain zinc fingers and Scm, Ph and MBT homology (SPM) domains. 34 The SPM domain mediates oligomerization of MBT domain proteins.…”

Physical activity and breast cancer survival: an epigenetic link through reduced methylation of a tumor suppressor gene L3MBTL1

“…Single-or double-strand deletion of L3MBTL2 and L3MBTL3 has been reported to occur in medulloblastoma [27]. L3MBTL4 was recently found to be frequently mutated or deleted with loss of function in breast cancer [28]. Currently, little is known about the role of L3MBTL1 in breast cancer and its relation to lifestyle factors such as physical activity.…”