Upstream Determinants of Estrogen Receptor-α Regulation of Metastatic Tumor Antigen 3 Pathway

Abstract

Although recent studies have shown a role of estrogen receptor-␣ (ER) in the regulation of epithelial-to-mesenchymal transition via MTA3, the role of upstream determinants of ER regulation of MTA3 and the underlying molecular mechanism remains unknown. Here we show that MTA3 gene regulation by ER is influenced by dynamic changes in levels of nuclear coregulators. MTA3 promoter has a functional ER element half-site with which MTA1 and HDACs interact under basal conditions. Upon estrogen stimulation, these corepressors are derecruited with concomitant recruitment of ER, leading to increased MTA3 transcription and expression. Genetic inactivation of MTA1 pathway promotes the ability of ER to up-regulate MTA3 expression, whereas knockdown of ER enhances MTA1 association with MTA3 gene. Modulation of ER functions, by corepressors (i.e. MTA1 and MTA1s) or coactivators (i.e. AIB1 and PELP1/MNAR), alters ER recruitment to MTA3 chromatin, MTA3 transcription, and expression of downstream epithelial-to-mesenchymal transition components. These studies provide novel insights into the transregulation of the MTA3 gene and reveal novel roles of upstream determinants in modifying the outcome of MTA3 axis and cell differentiation.The development of human breast cancer is promoted by estrogen stimulation of mammary epithelial cell growth. Estrogen receptor-␣ (ER) 1 is the major estrogen receptor in the human mammary epithelium. The binding of estrogen to ER triggers conformational changes that allow ER to bind to the 13-base-pair palindromic estrogen response element (ERE) in the target gene promoters and stimulates gene transcription thereby promoting the growth of breast cancer cells. The transcriptional activity of ER is affected by a number of regulatory cofactors including chromatin-remodeling complexes, coactivators, and corepressors (1-3).Recent findings have demonstrated that the NuRD-70 polypeptide of the nucleosome-remodeling complex is identical to metastatic tumor antigen 1 (MTA1) (4, 5) and that MTA1 physically interacts with HDAC1/2 (6, 7). The MTA1 gene is shown to correlate well with the metastatic potential of several human cell lines and cancers, including breast cancers (8 -11).Using in vitro models, Mazumdar et al. (12) have shown that MTA1 interacts with ER and represses ER transcription by recruiting HDAC to the ERE-containing target gene chromatin in breast cancer cells. MTA1-overexpressing breast cancer cells exhibit aggressive phenotypes (13). MTA1s, another family member, is a naturally occurring variant of MTA1 that contains a novel sequence of 33 amino acids with one potential nuclear receptor binding motif, LRILL. MTA1s inhibits ER nuclear signaling by sequestering ER in the cytoplasm but enhances ER cytoplasmic signaling and thus promotes tumorigenesis (14).One of the principal phenotypic changes in breast cancer metastasis is the increased tendency of the cancer cells to undergo epithelial-to-mesenchymal (EMT) transition that is characterized by reduced expression and consequently, functions of cell...

MTA1, a transcriptional activator of breast cancer amplified sequence 3

“…1B). Likewise, knockdown of endogenous MTA1 by MTA1-specific RNA interference (RNAi) (16) in MCF-7 cells decreased the amounts of BCAS3 mRNA and protein levels (Fig. 1C).…”

The human Mi-2/NuRD complex and gene regulation

“…MTA3 abundance correlates with the presence of ER-a in breast cancer cell lines (Fujita et al, 2003). This correlation results from direct activation of the MTA3 promoter by ER-a Mishra et al, 2004). Significantly, in the context of cultured breast cancer cells, MTA3 serves to repress transcription of genes implicated in invasive growth, such as the transcription factor Snail (Fujita et al, 2003).…”

MTA1 gene silencing inhibits invasion and alters the microRNA expression profile of human lung cancer cells

“…Only a few reports suggest that MTA1 may promote tumor progression by participating in chromatin remodeling (21,22), hypoxia signaling pathway (23), or the epithelial-mesenchymal transition pathway (24). miRNAs are small non-coding RNAs and have been implicated in the pathology of various diseases, including lung cancer.…”