Metastasis-associated genes (MTAs) represent a rapidly growing novel gene family. At present, there are three different known genes (MTA1, MTA2, and MTA3) and six reported
isoforms (MTA1, MTA1s, MTA1-ZG29p, MTA2, MTA3, MTA3L). MTA1, MTA2, and MTA3 are components of the
nucleosome remodeling and deacetylation complex, which is associated with
adenosine triphosphate-dependent chromatin remodeling and transcriptional regulation.
MTA proteins, as a part of the
NuRD complex (nuclear remodeling and deacetylation complex), are thought to modulate transcription by influencing the status of chromatin remodeling. MTA1 overexpression is closely correlated with an aggressive course in several human
carcinomas. Recent studies have shown that
growth factor stimulation of
breast cancer cells induces the expression of MTA1 and its interaction with and repression of the
estrogen receptor (ER) transactivation function, leading to enhanced anchorage-independent growth in vitro and
hormone independence. Furthermore, the status of the ER pathway modulates the expression of MTA3 as well as epithelial-to-mesenchymal transition in human
breast tumors. MTA1 expression is not restricted to
tumors; however, several normal mouse tissues and organs also express substantial levels of MTA1. Thus, MTA1 may play a role in both the physiologic and the pathologic states of cells. In Caenorhabditis elegans, MTA1-like genes regulate cell polarity, migration, embryonic patterning, and vulva development. In addition, two naturally occurring variants of MTA1, MTA1-ZG29p, and MTA1s have also been identified. ZG29p is an N-terminal truncated form of MTA1 and is present in the zymogen granules of the pancreas. In contrast, MTA1s is the C-terminal truncated form present in the cytoplasm. MTA1s binds and inhibits the nuclear functions of the ER by sequestering it to cytoplasm, stimulating the
mitogen-activated protein kinase pathway. Furthermore,
breast tumors with no or low ER in the nucleus exhibit elevated levels of MTA1s and cytoplasmic subcellular localization of the ER. This article reviews the current status of
MTA biochemistry and its implications for
tumor biology.