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10
MTAs in Cancer Invasion and
Metastasis
The Biology of Metastasis Promotion by MTAs
The MTA family genes are a well-studied family of metastasis associated genes. The
MTA1 occurs as a long and short isoforms which are generated by alternative mRNA
splicing and the family contains two other members MTA2 and MTA3. The MTAs are
expressed in many forms of cancer. Evidence is emerging of the involvement of MTAs
in EMT. Overexpression of MTAs has been correlated with invasion and aggressive
behaviour of many forms of cancer. They promote cancer cell migration by regulation
of cell adhesion proteins in consort with membrane-cytoskeletal linker proteins such
as Ezrin. MTAs also have been known to induce the expression of angiogenic agents.
MTA2 is believed to interact with p53 and interfere with its cell cycle regulatory func-
tion and apoptosis pathway (Toh and Nicolson, 2009; Pencil et al., 1993; Toh et al.,
1994, 1995; Mahoney et al., 2002).
MTA proteins repress genetic transcription by virtue of their function in histone
deacetylation and are involved with nucleosome remodelling and histone deacetylase
(NuRD) complex. MTA1 is a component of and engage with specific NuRD com-
plexes and interacts with HDAC-1. The MTA1-NuRD has been found to regulate
many genes of significance in the present context. Among them are ERα, c-myc and
the tumour suppressors BRAC1 and p53. The short isoform of MTA1 contains an ER
binding motif (LRILL) (Kumar et al., 2002). It is said to sequester cytoplasmic ERα
and in this way inactivates its transcription function. MTA1 has been reported to be
able to repress ERα activation by chromatin deacetylation of the ER-response element
of responsive genes (Toh and Nicolson, 2009). However, ERα and ERβ have oppos-
ing functions. The former promotes cell proliferation, but ERβ inhibits cell prolifera-
tion and invasion. It has also been apparent from recent work that ERβ2 can inhibit
ERα-mediated transactivation via oestrogen response element (Zhao et al., 2007b). The
long isoform of MTA is a co-repressor of ER (see UniProtKB Q13330). Also increased
expression of ER/MTA1-NuRD can influence ER/HER2 signalling which is crucially
important in TNBC. Therefore, the effects of MTA on ER need further exploration.
Whether enhanced non-genomic responses of ER might occur is a point for con-
sideration. The rapidity of response by oestrogens suggests that the signalling might
originate with ER at the membrane representing non-canonical pathways distinct
from conventional signalling by nuclear receptors (Ravelli et al., 1998; Nadal et al.,
2000; Ropero et al., 2002). Membrane bound ER, which may be relocated nuclear
ER, have been identified and these have been postulated to be GPCR30, the so-
called orphan receptor. Signalling by GPCR30 represents the non-genomic pathway.
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