Astrocyte Elevated Gene-1 is a Novel Prognostic Marker for Breast Cancer Progression and Overall Patient Survival

Abstract

Purpose: The present study was aimed at clarifying the expression of astrocyte elevated gene-1 (AEG-1), one of the target genes of oncogenic Ha-ras, in breast cancer and its correlation with clinicopathologic features, including the survival of patients with breast cancer. Experimental Design: The expression of AEG-1 in normal breast epithelial cells, breast cancer cell lines, and in four cases of paired primary breast tumor and normal breast tissue was examined using reverse transcription-PCR and Western blot. Real-time reverse transcription-PCR was applied to determine the mRNA level of AEG-1 in the four paired tissues, each from the same subject. Furthermore, AEG-1 protein expression was analyzed in 225 clinicopathologically characterized breast cancer cases using immunohistochemistry. Statistical analyses were applied to test for the prognostic and diagnostic associations. Results: Western blot and reverse transcription-PCR showed that the expression level of AEG-1 was markedly higher in breast cancer cell lines than that in the normal breast epithelial cells at both mRNA and protein levels. AEG-1 expression levels were significantly up-regulated by up to 35-fold in primary breast tumors in comparison to the paired normal breast tissue from the same patient. Immunohistochemical analysis revealed high expression of AEG-1in 100 of 225 (44.4%) paraffin-embedded archival breast cancer biopsies. Statistical analysis showed a significant correlation of AEG-1 expression with the clinical staging of the patients with breast cancer (P = 0.001), as well as with the tumor classification (P = 0.004), node classification (P = 0.026), and metastasis classification (P = 0.001). Patients with higher AEG-1 expression had shorter overall survival time, whereas patients with lower AEG-1 expression had better survival. Multivariate analysis suggested that AEG-1 expression might be an independent prognostic indicator for the survival of patients with breast cancer. Conclusions: Our results suggest that AEG-1 protein is a valuable marker of breast cancer progression. High AEG-1expression is associated with poor overall survival in patients with breast cancer.

Nuclear LYRIC/AEG-1 interacts with PLZF and relieves PLZF-mediated repression

“…Overexpressed LYRIC/AEG-1 reduces PLZF-mediated repression by abrogating the ability of PLZF to bind DNA, perhaps by sequestering PLZF to nuclear bodies. LYRIC/AEG-1 has been shown to be overexpressed during tumourigenesis (Li et al, 2008;Hu et al, 2009;Thirkettle et al, 2009) and our results suggest that this may lead to a reduction in PLZF-mediated repression. This would increase oncogene expression such as c-myc and a decrease in genes involved in apoptosis (Bernardo et al, 2007) (Figure 4d).…”

“…LYRIC/ AEG-1 is reported to be regulated by HA-RAS and c-myc (Lee et al, 2006), to suppress activators of apoptosis such as FOXO3a (Kikuno et al, 2007), and to activate nuclear factor-kB which regulates the expression of cell adhesion molecules implicated in cancer progression and metastasis . Recently, it has been shown that LYRIC/AEG-1 is overexpressed in breast and prostate tumourigenesis (Li et al, 2008;Hu et al, 2009;Thirkettle et al, 2009). We have shown that in benign prostate tissue LYRIC/ AEG-1 is localized predominantly in the nucleus and that loss of nuclear LYRIC/AEG-1 in cancer results in poor survival (Thirkettle et al, 2009).…”

“…Increasing evidence exists that LYRIC/AEG-1 may act as an oncogene and promote tumourigenesis, chemoresistance and metastases (Brown and Ruoslahti, 2004;Emdad et al, 2006;Kikuno et al, 2007;Ash et al, 2008;Li et al, 2008;Sarkar et al, 2008;Hu et al, 2009;Kwong and Chin, 2009;Thirkettle et al, 2009). LYRIC/ AEG-1 is reported to be regulated by HA-RAS and c-myc (Lee et al, 2006), to suppress activators of apoptosis such as FOXO3a (Kikuno et al, 2007), and to activate nuclear factor-kB which regulates the expression of cell adhesion molecules implicated in cancer progression and metastasis .…”

AEG‐1 induces gastric cancer metastasis by upregulation of eIF4E expression

“…AEG‐1/MTDH was subsequently found to mediate the metastasis of breast cancer 8. In recent years, AEG‐1 expression was found to be elevated and correlated with clinical tumour type, stage, metastasis and prognosis in a variety of cancers, including breast 9, lung 10, colorectal 11, cervical 12, 13, head and neck 14, hepatocellular 15 and gastric cancers 16, 17. AEG‐1 has been shown to be transcriptionally up‐regulated by Ha‐Ras‐activated PI3K and c‐Myc 18.…”

Astrocyte elevated gene-1 is a proliferation promoter in breast cancer via suppressing transcriptional factor FOXO1

“…Recently, a newly identified astrocyte elevated gene-1 (AEG-1), originally discovered as a protein induced in primary human fetal astrocytes infected with HIV-1 or treated with HIV gp120 or tumor necrosis factor-a, was implicated in promotion of oncogenesis, abrogation of cancer cell apoptosis and induction of metastasis (Kang et al, 2005;Emdad et al, 2006Emdad et al, , 2007Lee et al, 2006Lee et al, , 2008Kikuno et al, 2007;Ash et al, 2008;Li et al, 2008;Sarkar et al, 2008). It was found that ectopic expression of AEG-1 could augment anchorage-independent growth of nontumorigenic melanocytes and astrocytes (Kang et al, 2005;Emdad et al, 2007).…”