Expression and Clinical Significance of Activating Transcription Factor 3 in Human Breast Cancer

Document Type: Original Article

Authors

Department of General Surgery, the Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China

Abstract

 




Objective(s):
Breast cancer is the most common type of cancer among women worldwide. This study investigated the expression and clinical significance of activating transcription factor 3 (ATF3) in human breast cancer and its relationship with the clinical outcome of breast cancer.
 
Materials and Methods
: ATF3 expressions were detected in 114 primary breast cancer tissues and 114 adjacent normal tissues using immunohistochemistry (IHC) assay. Categorical variables were statistically compared by chi-square or Fisher’s exact test. Survival curves were evaluated using the Kaplan-Meier method and comparisons of survival rates were tested using a Log-rank test.
Results
: IHC analysis showed that the positive expression of ATF3 protein was detected in breast cancer tissue with a positive ratio of 76.3%, and the positive ATF3 expression in adjacent normal breast tissue was 13.2%, which is lower than that in breast cancer tissue samples (P<0.01). Furthermore, ATF3 expression showed significant correlation with TNM stage, invasion, lymph node metastasis and number of metastatic lymph nodes (P=0.038, P=0.029, P=0.026, and P=0.039 respectively), and did not correlate with patients’ age and tumor size (P>0.05). A significant difference in overall survival rate was found between the patients with positive expression of ATF3 protein and those with negative expression (P=0.041).
Conclusion
: Increased ATF3 expression participate in the tumorigenesis, invasion and metastasis of breast cancer, and ATF3 may be useful as a new prognostic indicator for breast cancer patients

Keywords


 

1. Chávarri-Guerra Y, Villarreal-Garza C, Liedke PE, Knaul F, Mohar A, Finkelstein DM,

et al. Breast cancer in Mexico: a growing challenge to health and the health system. Lancet Oncol 2012; 13:e335-e343.

2. Moody LC, Wen X, McKnight T, Chao C. Indications for sentinel lymph node biopsy in multifocal and multicentric breast cancer. Surgery 2012; 152:389-796.

3. Yan L, Della Coletta L, Powell KL, Shen J, Thames H, Aldaz CM,

et al. Activation of the canonical Wnt/beta-catenin pathway in ATF3-induced mammary tumors. PLoS One 2011; 6:e16515.

4. Yin X, Wolford CC, Chang YS, McConoughey SJ, Ramsey SA, Aderem A,

et al. ATF3, an adaptive-response gene, enhances TGF{beta} signaling and cancer-initiating cell features in breast cancer cells. J Cell Sci 2010; 123:3558-7565.

5. Patacsil D, Tran AT, Cho YS, Suy S, Saenz F, Malyukova I,

et al. Gamma-tocotrienol induced apoptosis is associated with unfolded protein response in human breast cancer cells. J Nutr Biochem 2012; 23:93-100.

6. Ameri K, Hammond EM, Culmsee C, Raida M, Katschinski DM, Wenger RH,

et al. Induction of activating transcription factor 3 by anoxia is independent of p53 and the hypoxic HIF signalling pathway. Oncogene 2007; 26:284-229.

7. Wang A, Arantes S, Yan L, Kiguchi K, McArthur MJ,

Sahin A,

et al. The transcription factor ATF3 acts as an oncogene in mouse mammary tumorigenesis. BMC Cancer 2008; 8:268.

8. Hackl C, Lang SA, Moser C, Mori A, Fichtner-Feigl S, Hellerbrand C,

et al. Activating transcription factor-3 (ATF3) functions as a tumor suppressor in colon cancer and is up-regulated upon heat-shock protein 90 (Hsp90) inhibition. BMC Cancer 2010; 10:668.

9. Pan YX, Chen H, Thiaville MM, Kilberg MS. Activation of the ATF3 gene through a co-ordinated amino acid-sensing response programme that controls transcriptional regulation of responsive genes following amino acid limitation. Biochem J 2007; 401:299-307.

10. Chromik AM, Hahn SA, Daigeler A, Flier A, Bulut D, May C,

et al. Gene expression analysis of cell death induction by taurolidine in different malignant cell lines. BMC Cancer 2010; 10:595.

11. Kawai M, Jin M, Nishimura J, Dewa Y, Saegusa Y, Matsumoto S,

et al. Hepatocarcinogenic susceptibility of fenofibrate and its possible mechanism of carcinogenicity in a two-stage hepatocarcinogenesis model of rasH2 mice. Toxicol Pathol 2002; 36:950-557.

12. Kawai M, Saegusa Y, Jin M, Dewa Y, Nishimura J, Harada T,

et al. Mechanistic study on hepatocarcinogenesis of piperonyl butoxide in mice. Toxicol Pathol 2009; 37:761-379.

13. Wu X, Nguyen BC, Dziunycz P, Chang S, Brooks Y, Lefort K

, et al. Opposing roles for calcineurin and ATF3 in squamous skin cancer. Nature 2010; 465:368-772.

14. Yin X, Dewille JW, Hai T. A potential dichotomous role of ATF3, an adaptive-response gene, in cancer development. Oncogene 2008; 27:2118-2127.

15. Thompson MR, Xu D, Williams BR. ATF3 transcription factor and its emerging roles in immunity and cancer. J Mol Med (Berl) 2009; 87:1053-1060.

16. Taherian A, Mazoochi T. Different expression of extracellular signal-regulated kinases (ERK) 1/2 and phospho-Erk proteins in MBA-MB-231 and MCF-7 Cells after chemotherapy with doxorubicin or docetaxel. Iran J Basic Med Sci 2012; 15: 669-777