MTA1 overexpression correlates significantly with tumor grade and angiogenesis in human breast cancers

Abstract

F emale breast cancer is a major public health problem, with more than 1 000 000 cases occurring worldwide annually. (1) Despite major advances that have been made in understanding the biological and clinical nature of the disease, the therapeutic problem persists. Therefore, identification of novel breast cancer biomarkers could be utilized as possible therapeutic targets or prognostic predictors that would contribute to the advancement of breast cancer treatment.Metastasis associated antigen 1 (MTA1) was originally identified by differential screening of a cDNA library from highly metastatic and non-metastatic rat mammary adenocarcinoma cell lines. (2)(3)(4) The expression level is estimated to be four-fold higher in the highly metastatic cell line MTLn3 than in the non-metastatic cell line MTC4. (2) The mRNA expression level of the human homolog of this gene is approximately four-times higher in a metastatic cell line (MDA-MB-231) than in a non-invasive and non-metastatic cell line (MDA-MB-468) in nude mice. (2) MTA1 is expressed physiologically at low levels in all normal tissue, except the testis. (2) Several studies have identified various roles for MTA1 in normal mammary gland development and human breast cancer progression, including cell proliferation and invasiveness. A study with MTA1 transgenic mice reveals that MTA1 dysregulation in mammary epithelium causes increased cell proliferation, hyper-branched ductal structure formation and precocious development, and results in the development of hyperplastic nodules and mammary gland tumors in virgin mice. (5) The growth of human MDA-MB-231 breast cancer cells is inhibited after treatment with MTA1 antisense phosphorothioate oligonucleotides. (6) MTA1 overexpression in non-invasive breast cancer MCF-7 cells yields larger colony formation in soft agar, augmented colony formation, as well as increased invasiveness in a Boyden chamber assay. (7) Thus, MTA1 may play an important role in tumorigenesis and tumor aggressiveness. However, the role of MTA1 in surgically resected breast cancer tissue with its clinicopathological parameters has not been investigated to date. Therefore, we analyzed the relationship between MTA1 expression and variable clinicopathological features.Tumor microenvironment is known to play an active role in tumor progression through adhesion molecules, angiogenesis and stromal host cells. (8)(9)(10) Previous experimental studies highlight the role of angiogenesis in tumor progression, such as tumor growth and blood-borne metastasis. (11,12) In breast cancer, the overall results of reported studies suggest that human breast cancer is an angiogenic-dependent tumor, and anti-angiogenic therapy may be beneficial for breast cancer patients. (13,14) Therefore, we analyzed the possible role of MTA1 in tumor angiogenesis of breast cancer by counting intratumoral microvessels, which is widely used to estimate tumor angiogenesis. (15) In the present study, we report a statistically significant correlation between MTA1 gene expression and increased...

MTA1-mediated transcriptional repression of BRCA1 tumor suppressor gene

“…Multiple studies have shown a correlation between loss of BRCA1 expression and increased metastatic disease. In the light of these findings and because MTA1 is widely overexpressed in human cancers including breast cancer (Toh et al, 1994;Nawa et al, 2000;Jang et al, 2006), and its overexpression has been associated with metastasis, it appears that the MTA1-containing NuRD complex exerts a repressive effect on BRCA1 expression. Consistent with this notion was the relatively significant decrease in the mRNA and protein levels of BRCA1 and its target PARP1 that we observed in MCF7/MTA1 stable cells stably when compared with control MCF7/pcDNA cells (Figure 1).…”

“…Indeed, MTA1 is overexpressed in a variety of human cancers including cancers of the breast, ovary, lung, gastrointestinal system and colorectum (Toh et al, 1994(Toh et al, , 1999Hamatsu et al, 2003;Balasenthil et al, 2006;Jang et al, 2006;Martin et al, 2006). It also plays an important role in metastasis and tumor aggressiveness (Toh et al, 1994(Toh et al, , 1999Jang et al, 2006).…”

Metastatic tumor antigen 1 is closely associated with frequent postoperative recurrence and poor survival in patients with hepatocellular carcinoma

“…[27][28][29][30] MTA1 plays an important role in the adverse course of various human cancers, including breast, prostate, lung, colorectal, gastric, and esophageal cancers, through migration and invasion of cancer cells toward surrounding and distant tissues. [17][18][19][20][21][22][23][24] In HCC, only a small number of studies have examined the role of MTA1 in vascular invasion and survival after treatment. Moon et al 25 reported that high MTA1 expression levels were correlated with large tumors and vascular invasion, based on analysis of paraffin sections from 45 HCC specimens.…”

“…[14][15][16] Thus, it has been reported that MTA1 overexpression is closely correlated with an aggressive course in several human cancers, such as breast, prostate, colorectal, gastric, and esophageal cancers. [17][18][19][20][21][22][23][24] However, few data are available regarding the role of MTA1 in invasion, recurrence, and survival in HCC patients. 25,26 In this study, we examined whether the high expression levels of MTA1 in HCC tissues can affect the recurrence of HCC after surgical resection and consequently affect patient survival.…”

Metastatic events of MDA-MB-231 cells induced by angiogenic factors VEGF or MYA1 are inhibited by Tinospora cordifolia hexane fraction (tchf)

“…It is known that MTA1 has important and critical roles in the angiogenesis and progression of a wide variety of cancers. Several studies have identified various roles for MTA1 in normal mammary gland development and human breast cancer progression, including cell proliferation and invasiveness [8]. MTA1 also enhances angiogenesis by stabilization of HIF-1α [9].…”