AZU-1: A Candidate Breast Tumor Suppressor and Biomarker for Tumor Progression

Abstract

To identify genes misregulated in the final stages of breast carcinogenesis, we performed differential display to compare the gene expression patterns of the human tumorigenic mammary epithelial cells, HMT-3522-T4-2, with those of their immediate premalignant progenitors, HMT-3522-S2. We identified a novel gene, called anti-zuai-1 (AZU-1), that was abundantly expressed in non-and premalignant cells and tissues but was appreciably reduced in breast tumor cell types and in primary tumors. The AZU-1 gene encodes an acidic 571-amino-acid protein containing at least two structurally distinct domains with potential protein-binding functions: an N-terminal serine and proline-rich domain with a predicted immunoglobulin-like fold and a C-terminal coiled-coil domain. In HMT-3522 cells, the bulk of AZU-1 protein resided in a detergent-extractable cytoplasmic pool and was present at much lower levels in tumorigenic T4-2 cells than in their nonmalignant counterparts. Reversion of the tumorigenic phenotype of T4-2 cells, by means described previously, was accompanied by the up-regulation of AZU-1. In addition, reexpression of AZU-1 in T4-2 cells, using viral vectors, was sufficient to reduce their malignant phenotype substantially, both in culture and in vivo. These results indicate that AZU-1 is a candidate breast tumor suppressor that may exert its effects by promoting correct tissue morphogenesis.

The transforming acidic coiled coil proteins interact with nuclear histone acetyltransferases

“…On the other, the TACC1 protein has been shown to be significantly reduced in 50% of resected breast tumors, compared to normal levels, suggesting that TACC1 may be a breast tumor suppressor gene (Conte et al, 2002(Conte et al, , 2003. TACC2 has also been suggested to be a candidate tumor suppressor gene (Chen et al, 2000;Conte et al, 2003;Lauffart et al, 2003). Overexpression of the short isoform, TACC2s, can reduce the in vitro tumorigenic properties of estrogen receptor negative breast cancer cell lines (Lauffart et al, 2003); an effect that is apparently mediated by the conserved TACC domain (Chen et al, 2000;Still et al, unpublished).…”

TACC2 (transforming acidic coiled‐coil protein 2) in breast carcinoma as a potent prognostic predictor associated with cell proliferation

“…Significance of TACC2 in breast cancer is controversial. TACC2 was identified as a putative breast tumor suppressor 11 and overexpression of TACC2 reverted a malignant phenotype to a benign phenotype 13. On the other hand, single‐nucleotide polymorphisms (SNPs) in TACC2 were significantly associated with a risk of low‐grade breast cancer 25, and TACC2 mRNA expression was significantly correlated with shorter disease‐free survival of breast carcinomas patients 12.…”

“…On the other hand, TACC2 has been demonstrated to promote androgen‐mediated growth in the prostate cancer 10, but previous evidences of TACC2 in breast cancer were inconsistent and its significance remains largely unclear. TACC2 was mentioned as a putative breast tumor suppressor 11, whereas Cheng et al. (2010) reported that high expression of TACC2 mRNA in tumor tissue was associated with shorter disease‐free survival of breast carcinoma patients by real‐time PCR analysis 12.…”

TTK kinase is essential for the centrosomal localization of TACC2

“…Bissell and colleagues have recently isolated TACC2/Azu-1 in a screen aimed for identification of stage-specific tumor suppressors during tumorigenesis of human breast cancer [14]. They found that TACC2/Azu1 was downregulated not only in tumorigenic mammary epithelial cells, but also in primary tumors.…”

“…Although there are three TACC proteins in human, their tissue-specific expression and distinct spatial-temporal regulation of subcellular distribution argue for functional specificity among the three proteins. Interestingly, TACC2 has also recently been identified as a potential tumor suppressor in a search for genes differentially expressed between malignant mammary epithelial cells and their immediate non-malignant progenitors [14]. TACC2 was often found to be downregulated as the cells progressed from a benign to a malignant phenotype of breast epithelial cells [14].…”