MTA3, a Mi-2/NuRD Complex Subunit, Regulates an Invasive Growth Pathway in Breast Cancer

Abstract

Estrogen receptor is a key regulator of proliferation and differentiation in mammary epithelia and represents a crucial prognostic indicator and therapeutic target in breast cancer. Mechanistically, estrogen receptor induces changes in gene expression through direct gene activation and also through the biological functions of target loci. Here, we identify the product of human MTA3 as an estrogen-dependent component of the Mi-2/NuRD transcriptional corepressor in breast epithelial cells and demonstrate that MTA3 constitutes a key component of an estrogen-dependent pathway regulating growth and differentiation. The absence of estrogen receptor or of MTA3 leads to aberrant expression of the transcriptional repressor Snail, a master regulator of epithelial to mesenchymal transitions. Aberrant Snail expression results in loss of expression of the cell adhesion molecule E-cadherin, an event associated with changes in epithelial architecture and invasive growth. These results establish a mechanistic link between estrogen receptor status and invasive growth of breast cancers.

Snail Mediates E-Cadherin Repression by the Recruitment of the Sin3A/Histone Deacetylase 1 (HDAC1)/HDAC2 Complex

“…Understanding the mechanisms involved in the regulation of Snail and other E-cadherin repressors is an important issue to advance in our understanding of the tumor invasion process. Recently it was reported that the Mi-2/NuRD corepressor complex is involved in the transcriptional repression of Snail in an estrogen receptor-dependent fashion in breast cancer cells (18). This information suggests additional levels of regulation for the Snail-mediated repression of E-cadherin, involving the participation of at least two corepressor complexes.…”

Epigenetics provides a new generation of oncogenes and tumour-suppressor genes

“…Metastasis-associated gene 1 overexpression is associated with the most malignant behaviour in several human tumours. Metastasisassociated gene 3 has a predominant role in lymphoma and breast cancer, in the latter leading to aberrant expression of the transcriptional repressor Snail and loss of expression of the celladhesion molecule E-cadherin, an event associated with invasive growth of breast cancers (Fujita et al, 2003).…”

Expression of the plasmacytoid dendritic cell marker BDCA-2 supports a spectrum of maturation among CD4+ CD56+ hematodermic neoplasms

“…Plasmacytoid dendritic cells, totaling 5 Â 10 6 were isolated using the MACS separation and monoclonal anti-BDCA-2 (Miltenyi Biotec). RNA was purified 24 followed by reverse transcription using the gene specific oligonucleotide primer, BDCA-2-R (5 0 -CTCGAGTATG TAGATCTTCT TCATCTT-3 0 ). Specific PCR employed primers BDCA-2-F (5 0 -CATATGGTGC CTGAAGAAGA GC-3 0 ) and BDCA-2-R. DNA sequencing confirmed the correct full-length coding region, 20 which was subcloned into the mammalian expression vector pcDNA3.1 þ (Invitrogen) to generate pFL.BDCA-2.…”