Expressions of EphA2 receptor and its ligand EphrinA1 in invasive ductal carcinoma of breast and their clinical significances_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Authors：

YANG Gui ¹ ,  LI Zhuang ¹ , ZHANG Bensi ² , BIAN Siyuan ² , ZHANG Hongrong ¹ , CHEN Bo ¹

1. Department of Surgery, Affiliated Hospital of Dali University, Dali, Yunnan 671000, P.R.China;
2. Department of Anatomy, College of Preclinical Medicine, Dali University, Dali, Yunnan 671000, P.R.China;

Corresponding author：

LI Zhuang, Email: li_zhuang126@126.com

Keywords：

invasive ductal carcinoma of breast; EphA2; EphrinA1; immunohistochemistry; in situ hybridization

DOI：

10.7507/1007-9424.201610044

Video：

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Objective To investigate expressions of EphA2 and EphrinA1 in invasive ductal carcinoma of breast and to explore their clinical significances. Method The protein and mRNA expressions of EphA2 and EphrinA1 in 30 breast fibroma tissues, 30 breast cystic hyperplasia tissues, and 100 invasive ductal carcinoma of breast tissues were detected by immunohistochemistry andin situ hybridization respectively, and correlation between them and relations between their expressions in invasive ductal carcinoma of breast tissues and clinicopathologic factors were analyzed. Results ① The results of the immunohistochemistry andin situ hybridization tests showed that the protein and mRNA expressions of EphA2 and EphrinA1 in the invasive ductal carcinoma of breast tissues were significantly higher than those in the breast fibroma tissue (P<0.001) and breast cystic hyperplasia tissue (P<0.001). ② The positive expressions of EphA2 and EphrinA1 protein and mRNA were associated with the lymph node metastasis, histological grade, and TNM stage (P<0.05), in other words, which in the invasive ductal carcinoma of breast patients with lymph node metastasis, high histological grade, and high TNM stage were higher. However, which were not associated with the age and the tumor diameter (P>0.05). ③ The positive protein expressions or positive mRNA expressions in the invasive ductal carcinoma of breast tissues all had positive correlations between the EphA2 and the EphrinA1 (protein:r_s =0.999,P<0.01; mRNA:r_s =0.942,P<0.01). Conclusions EphA2 and EphrinA1 might be involved in carcinogenesis and development procedures of invasive ductal carcinoma of breast. Combined detection of EphA2 and EphrinA1 could help to predict clinical and pathologic characteristics of invasive ductal carcinoma of breast. They might provide a new target for clinical medication, prognosis, and targeted therapy.

Citation： YANG Gui, LI Zhuang, ZHANG Bensi, BIAN Siyuan, ZHANG Hongrong, CHEN Bo. Expressions of EphA2 receptor and its ligand EphrinA1 in invasive ductal carcinoma of breast and their clinical significances. CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY, 2017, 24(5): 555-561. doi: 10.7507/1007-9424.201610044 Copy

1.	Drescher U. Eph family functions from an evolutionary perspective. Curr Opin Genet Dev, 2002, 12(4): 397-402.
2.	Suetterlin P, Marler KM, Drescher U. Axonal ephrinA/EphA interactions, and the emergence of order in topographic projections. Semin Cell Dev Biol, 2012, 23(1): 1-6.
3.	Kamat AA, Coffey D, Merritt WM, et al. EphA2 overexpression is associated with lack of hormone receptor expression and poor outcome in endometrial cancer. Cancer, 2009, 115(12): 2684-2692.
4.	Zeng G, Hu Z, Kinch MS, et al. High-level expression of EphA2 receptor tyrosine kinase in prostatic intraepithelial neoplasia. Am J Pathol, 2003, 163(6): 2271-2276.
5.	吕西, 李徐生, 张有成, 等. EphA2 mRNA 和 VEGF 在肝癌细胞中的表达及其关系. 中华肝胆外科杂志, 2006, 12(10): 680-683.
6.	蒋学风, 唐琼兰, 何欣欣, 等. EphA2 及其配体在子宫内膜样腺癌中的表达及其血管生成的关系. 中国病理生理杂志, 2013, 29(5): 857-861.
7.	蒋萍, 李景和, 罗庚求, 等. EphA2 对结肠癌细胞株 HCT116 中 VEGF 和 MMP9 蛋白表达的影响. 中南大学学报(医学版), 2007, 32(4): 679-683.
8.	Aasheim HC, Patzke S, Hjorthaug HS, et al. Characterization of a novel Eph receptor tyrosine kinase, EphA10, expressed in testis. Biochim Biophys Acta, 2005, 1723(1-3): 1-7.
9.	O’Leary DD, Wilkinson DG. Eph receptors and ephrins in neural development. Curr Opin Neurobiol, 1999, 9(1): 65-73.
10.	Sasaki E, Hikono H, Kaku Y, et al. ephA9, a novel avian receptor tyrosine kinase gene. Gene, 2003, 316: 103-110.
11.	赵玉斌, 张少华, 张积仁, 等. ER、PR 和 EphA2 在乳腺癌中的表达及临床意义. 实用肿瘤杂志, 2010, 25(1): 41-44.
12.	Nakamoto M. Eph receptors and ephrins. Int J Biochem Cell Biol, 2000, 32(1): 7-12.
13.	Tandon M, Vemula SV, Mittal SK. Emerging strategies for EphA2 receptor targeting for cancer therapeutics. Expert Opin Ther Targets, 2011, 15(1): 31-51.
14.	Zelinski DP, Zantek ND, Stewart JC, et al. EphA2 overexpression causes tumorigenesis of mammary epithelial cells. Cancer Res, 2001, 61(5): 2301-2306.
15.	Fang WB, Brantley-Sieders DM, Parker MA, et al. A kinase-dependent role for EphA2 receptor in promoting tumor growth and metastasis. Oncogene, 2005, 24(53): 7859-7868.
16.	Thaker PH, Deavers M, Celestino J, et al. EphA2 expression is associated with aggressive features in ovarian carcinoma. Clin Cancer Res, 2004, 10(15): 5145-5150.
17.	Choi K, Creighton CJ, Stivers D, et al. Transcriptional profiling of non-small cell lung cancer cells with activating EGFR somatic mutations. PLoS One, 2007, 2(11): e1226.
18.	韩丽萍, 董子明, 乔玉环, 等. 卵巢癌组织中 EphA2 受体蛋白的表达. 郑州大学学报(医学版), 2005, 40(2): 308-311.
19.	Kaenel P, Mosimann M, Andres AC. The multifaceted roles of Eph/ephrin signaling in breast cancer. Cell Adh Migr, 2012, 6(2): 138-147.
20.	Brantley-Sieders DM, Fang WB, Hwang Y, et al. Ephrin-A1 facilitates mammary tumor metastasis through an angiogenesis-dependent mechanism mediated by EphA receptor and vascular endothelial growth factor in mice. Cancer Res, 2006, 66(21): 10315-10324．.
21.	Merritt WM, Kamat AA, Hwang JY, et al. Clinical and biological impact of EphA2 overexpression and angiogenesis in endometrial cancer. Cancer Biol Ther, 2010, 10(12): 1306-1314．.
22.	Valladares A, Hernández NG, Gómez FS, et al. Genetic expression profiles and chromosomal alterations in sporadic breast cancer in Mexican women. Cancer Genet Cytogenet, 2006, 170(2): 147-151.
23.	Herrem CJ, Tatsumi T, Olson KS, et al. Expression of EphA2 is prognostic of disease-free interval and overall survival in surgically treated patients with renal cell carcinoma. Clin Cancer Res, 2005, 11(1): 226-231.
24.	Huang J, Xiao D, Li G,et al. EphA2 promotes epithelial-mesenchymal transition through the Wnt/β-catenin pathway in gastric cancer cells. Oncogene, 2014, 33(21): 2737-2747.
25.	Miyazaki K, Inokuchi M, Takagi Y, et al. EphA4 is a prognostic factor in gastric cancer. BMC Clin Pathol, 2013, 13(1): 19.

1. Drescher U. Eph family functions from an evolutionary perspective. Curr Opin Genet Dev, 2002, 12(4): 397-402.
2. Suetterlin P, Marler KM, Drescher U. Axonal ephrinA/EphA interactions, and the emergence of order in topographic projections. Semin Cell Dev Biol, 2012, 23(1): 1-6.
3. Kamat AA, Coffey D, Merritt WM, et al. EphA2 overexpression is associated with lack of hormone receptor expression and poor outcome in endometrial cancer. Cancer, 2009, 115(12): 2684-2692.
4. Zeng G, Hu Z, Kinch MS, et al. High-level expression of EphA2 receptor tyrosine kinase in prostatic intraepithelial neoplasia. Am J Pathol, 2003, 163(6): 2271-2276.
5. 吕西, 李徐生, 张有成, 等. EphA2 mRNA 和 VEGF 在肝癌细胞中的表达及其关系. 中华肝胆外科杂志, 2006, 12(10): 680-683.
6. 蒋学风, 唐琼兰, 何欣欣, 等. EphA2 及其配体在子宫内膜样腺癌中的表达及其血管生成的关系. 中国病理生理杂志, 2013, 29(5): 857-861.
7. 蒋萍, 李景和, 罗庚求, 等. EphA2 对结肠癌细胞株 HCT116 中 VEGF 和 MMP9 蛋白表达的影响. 中南大学学报(医学版), 2007, 32(4): 679-683.
8. Aasheim HC, Patzke S, Hjorthaug HS, et al. Characterization of a novel Eph receptor tyrosine kinase, EphA10, expressed in testis. Biochim Biophys Acta, 2005, 1723(1-3): 1-7.
9. O’Leary DD, Wilkinson DG. Eph receptors and ephrins in neural development. Curr Opin Neurobiol, 1999, 9(1): 65-73.
10. Sasaki E, Hikono H, Kaku Y, et al. ephA9, a novel avian receptor tyrosine kinase gene. Gene, 2003, 316: 103-110.
11. 赵玉斌, 张少华, 张积仁, 等. ER、PR 和 EphA2 在乳腺癌中的表达及临床意义. 实用肿瘤杂志, 2010, 25(1): 41-44.
12. Nakamoto M. Eph receptors and ephrins. Int J Biochem Cell Biol, 2000, 32(1): 7-12.
13. Tandon M, Vemula SV, Mittal SK. Emerging strategies for EphA2 receptor targeting for cancer therapeutics. Expert Opin Ther Targets, 2011, 15(1): 31-51.
14. Zelinski DP, Zantek ND, Stewart JC, et al. EphA2 overexpression causes tumorigenesis of mammary epithelial cells. Cancer Res, 2001, 61(5): 2301-2306.
15. Fang WB, Brantley-Sieders DM, Parker MA, et al. A kinase-dependent role for EphA2 receptor in promoting tumor growth and metastasis. Oncogene, 2005, 24(53): 7859-7868.
16. Thaker PH, Deavers M, Celestino J, et al. EphA2 expression is associated with aggressive features in ovarian carcinoma. Clin Cancer Res, 2004, 10(15): 5145-5150.
17. Choi K, Creighton CJ, Stivers D, et al. Transcriptional profiling of non-small cell lung cancer cells with activating EGFR somatic mutations. PLoS One, 2007, 2(11): e1226.
18. 韩丽萍, 董子明, 乔玉环, 等. 卵巢癌组织中 EphA2 受体蛋白的表达. 郑州大学学报(医学版), 2005, 40(2): 308-311.
19. Kaenel P, Mosimann M, Andres AC. The multifaceted roles of Eph/ephrin signaling in breast cancer. Cell Adh Migr, 2012, 6(2): 138-147.
20. Brantley-Sieders DM, Fang WB, Hwang Y, et al. Ephrin-A1 facilitates mammary tumor metastasis through an angiogenesis-dependent mechanism mediated by EphA receptor and vascular endothelial growth factor in mice. Cancer Res, 2006, 66(21): 10315-10324．.
21. Merritt WM, Kamat AA, Hwang JY, et al. Clinical and biological impact of EphA2 overexpression and angiogenesis in endometrial cancer. Cancer Biol Ther, 2010, 10(12): 1306-1314．.
22. Valladares A, Hernández NG, Gómez FS, et al. Genetic expression profiles and chromosomal alterations in sporadic breast cancer in Mexican women. Cancer Genet Cytogenet, 2006, 170(2): 147-151.
23. Herrem CJ, Tatsumi T, Olson KS, et al. Expression of EphA2 is prognostic of disease-free interval and overall survival in surgically treated patients with renal cell carcinoma. Clin Cancer Res, 2005, 11(1): 226-231.
24. Huang J, Xiao D, Li G,et al. EphA2 promotes epithelial-mesenchymal transition through the Wnt/β-catenin pathway in gastric cancer cells. Oncogene, 2014, 33(21): 2737-2747.
25. Miyazaki K, Inokuchi M, Takagi Y, et al. EphA4 is a prognostic factor in gastric cancer. BMC Clin Pathol, 2013, 13(1): 19.

CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Expressions of EphA2 receptor and its ligand EphrinA1 in invasive ductal carcinoma of breast and their clinical significances

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