Document Type : Original Article

Authors

1 Department of Pathology, Faculty of Medicine, Zagazig University, Zagazig, Egypt

2 Department of Anatomy and Embryology, Faculty of Medicine, Zagazig University, Zagazig, Egypt

3 Department of Clinical Oncology and Nuclear Medicine, Faculty of Medicine, Zagazig University, Zagazig, Egypt

4 Department of General Surgery, Faculty of Medicine, Zagazig University, Zagazig, Egypt

Abstract

Background: The preponderance of breast cancer-related deaths are the result of local invasion and distant metastasis; therefore, it is necessary to identify the factors underlying invasion and metastasis in order to develop novel treatment strategies and improve the survival of patients. In this regard, this study aimed to investigate the immunohistochemical expression and prognostic impact of aquaporin-3 (AQP3) and certain markers associated with epithelial-mesenchymal transition concerning invasive breast carcinoma of no special type.
Method: Immunohistochemical expressions of AQP3, vimentin and E-cadherin were performed in 50 paraffin embedded specimens of such cases. We also assessed the relationship of their expressions with the clinicopathological variables and patients’ disease-free survival and overall survival.
Results: There were significant associations between positive AQP3 and positive vimentin expressions and high tumor grade, large tumor size, lymph node metastasis, and advanced tumor stage. On other hand, negative E-cadherin expression had a significant correlation with high tumor grade, large tumor size, lymph node metastasis, distant metastasis, and advanced tumor stage. A significant association also existed between positive AQP3, positive vimentin and negative E-cadherin expressions and high tumor recurrence, short ‘three-year’ disease-free survival and overall survival.
Conclusion: Positive AQP3, positive vimentin, and negative E-cadherin expressions are known as adverse prognostic markers and may predict survival in invasive breast carcinoma of no special type. It is proposed that AQP3 might play a role in breast cancer progression, invasion, and metastasis through induction of epithelial-mesenchymal transition.

Keywords

How to cite this article:

Attia AS, Mohamed AH, Hegazy AA, Elwan A, Salah M, Abdelhamid MI, et al. Prognostic value of aquaporin-3, vimentin and e-cadherin expressions in invasive breast carcinoma: An immunohistochemical study. Middle East J Cancer. 2020;11(4): 423-37. doi: 10.30476/mejc.2020.81564.1024.

 
1.      Ibrahim AS, Khaled HM, Mikhail NN, Baraka H, Kamel H. Cancer incidence in egypt: results of the national population-based cancer registry program. J Cancer Epidemiol. 2014;2014:437971. doi: 10.1155/2014/437971.
 
2.      Shibata K, Suzuki A, Watanabe T, Takasu N, Hirai L, Kimura W.ZEP-1 and E-cadherin expression may predict recurrence –free survival in patient with invasive ductal breast carcinoma. Yamagata Med J. 2015;33(2):61-69. doi: 10.150220003468.
 
3.    Benzina S, Beauregard AP, Guerrette R, Jean S, Faye MD, Laflamme M, et al. Pax-5 is a potent regulator of E-cadherin and breast cancer malignant processes. Oncotarget. 2017;8(7):12052-12066. doi: 10.18632/oncotarget.14511.
 
4.    Heerboth S, Housman G, Leary M, Longacre M, Byler S, Lapinska K, et al. EMT and tumor metastasis. Clin Transl Med. 2015;4:6. doi:10.1186/s40169-015-0048-3.
 
5.      Hegazy A. Clinical embryology for medical students and postgraduate doctors. Berlin: LAP ‘Lambert Academic Publishing’; 2014. 
 
6.      Huang X, Zhang C, Cai J, Shi G, Ke A, Dong Z, et al. Comprehensive multiple molecular profile of epithelial mesenchymal transition in intrahepatic cholangiocarcinoma patients. PLoS One. 2014; 9(5): e96860.
 
7.      Chen J, Wang T, Zhou YC, Gao F, Zhang ZH, Xu H, et al. Aquaporin 3 promotes epithelial-mesenchymal transition in gastric cancer.J Exp Clin Cancer Res. 2014;33:38. doi: 10.1186/1756-9966-33-38.
 
8.     Kang S, Chae YS, Lee SJ, Kang BW, Kim JG, Kim WW, et al. Aquaporin 3 Expression predicts survival in patients with HER2-positive early breast cancer. Anticancer Res. 2015;35(5):2775-82.
 
9.      Marlar S, Jensen HH, Login FH, Nejsum LN. Aquaporin-3 in Cancer. Int J Mol Sci. 2017;18(10). pii: E2106. doi: 10.3390/ijms18102106.
 
10.  Maitham AK, Luqmani YA.Role of aquaporins in breast cancer progression and metastasis. Chapter 4: Aquaporin-3 in cancer. 2016.p.59-83. Available at: http://dx.doi.org/10.5772/64446.
 
11.  Chen R, Shi Y, Amiduo R, Tuokan T, Suzuk L.Expression and prognostic value of aquaporin 1, 3 in cervical carcinoma in women of Uygur ethnicity from Xinjiang, China. PLoS One. 2014;9(6): e98576. doi:10.1371/journal. pone.0098576.
 
12.  Ji C, Cao C, Lu S, Kivlin R, Amaral A, Kouttab N, et al. Curcumin attenuates EGF-induced AQP3 up-regulation and cell migration in human ovarian cancer cells. Cancer Chemother Pharmacol. 2008;62(5):857-65. doi: 10.1007/s00280-007-0674-6.
 
13.  Hemalatha A, Suresh TN, Harendra Kumar ML. Expression of vimentin in breast carcinoma, its correlation with Ki67 and other histopathological parameters. Indian J Cancer. 2013;50:189-94
 
14.  Ricciardi GR, Adamo B, Ieni A, Licata L, Cardia R, Ferraro G, et al. Androgen receptor (AR), E-cadherin, and Ki-67 as emerging targets and novel prognostic markers in triple-negative breast cancer (TNBC) patients. PLoS One.  2015;10(6):e0128368.
 
15.  Abdelrahman AE, Arafa SA, Ahmed RA. Prognostic Value of twist-1, E-cadherin and EZH2 in prostate cancer: An immunohistochemical study. Turk Patoloji Derg. 2017;33(3):198-210 doi: 10.5146/tjpath.2016.01392.
 
16.  Ashaie MA, Chowdhury EH.Cadherins: the superfamily critically involved in breast cancer. Curr Pharm Des. 2016; 22:616-38
 
17.  Lakhani SR, Ellis IO, Schnitt SJ, Tan PH, van de Vijver MJ.WHO classification of tumors of the breast. 4th ed. Lyon, France: IARC Press; 2012.
 
18.  Edge SB, Byrd DR, Compton CC, Fritz AG, Greene FL, Trotti A. AJCC cancer staging manual, 7th ed. New York: Springer; 2010.
 
19.  Huang YT, Zhou J, Shi S, Xu HY, Qu F, Zhang D, et al. Identification of estrogen response element in aquaporin-3 gene that mediates estrogen-induced cell migration and invasion in estrogen receptor-positive breast cancer. Sci Rep. 2015; 5:12484.  doi: 10.1038/srep12484.
 
20.  Savagner P. The epithelial-mesenchymal transition (EMT) phenomenon. Ann Oncol. 2010;21 Suppl 7:vii89-92. doi: 10.1093/annonc/mdq292.
 
21.  Jeong H, Ryu YJ, An J, Lee Y, Kim A. Epithelial-mesenchymal transition in breast cancer correlates with high histological grade and triple-negative phenotype. Histopathology. 2012;60(6B):E87-95. doi:10.1111/j.1365-2559.2012.04195.x.
 
22.  Rodriguez-Pinilla SM, Sarrio D, Honrado E, Hardisson D, Calero F, et al.  Prognostic significance of basal-like phenotype and fascin expression in node-negative invasive breast carcinomas. Clin Cancer Res. 2006; 12: 1533–1539.
 
23.  Sarrió D, Rodriguez-Pinilla SM, Hardisson D, Cano A, Moreno-Bueno G, Palacios J. Epithelial-mesenchymal transition in breast cancer relates to the basal-like phenotype. Cancer Res. 2008;68(4):989-97. doi:10.1158/0008-5472.CAN-07-2017.
 
24.  Mendez MG, Kojima S, Goldman RD. Vimentin induces changes in cell shape, motility, and adhesion during the epithelial to mesenchymal transition. FASEB J. 2010;24(6):1838-51. doi: 10.1096/fj.09-151639.
 
25.  Neve RM, Chin K, Fridlyand J, Yeh J, Baehner FL, Fevr T, et al. A collection of breast cancer cell lines for the study of functionally distinct cancer subtypes. Cancer Cell. 2006;10(6):515-27.
 
26.  Hendrix MJ, Seftor EA, Seftor RE, Trevor KT. Experimental co-expression of vimentin and keratin intermediate filaments in human breast cancer cells results in phenotypic interconversion and increased invasive behavior. Am J Pathol. 1997;150(2):483-95.
 
27.  Vuoriluoto K, Haugen H, Kiviluoto S, Mpindi JP, Nevo J, Gjerdrum C, et al. Vimentin regulates EMT induction by Slug and oncogenic H-Ras and migration by governing Axl expression in breast cancer. Oncogene. 2011;30(12):1436-48. doi: 10.1038/onc.2010.509.
 
28.  Karihtala P, Auvinen P, Kauppila S, Haapasaari KM, Jukkola-Vuorinen A, Soini Y. Vimentin, zeb1 and Sip1 are up-regulated in triple-negative and basal-like breast cancers: association with an aggressive tumour phenotype. Breast Cancer Res Treat. 2013;138(1):81-90. doi: 10.1007/s10549-013-2442-0.
 
29.  Calaf G, Balajee AS, Montalvo-villagra MT, leon M, Navarrete MD, González alvarez R, et al. Vimentin and Notch as biomarkers for breast cancer progression. Oncol Lett. 2014; 7(3): 721-7. doi: 10.3892/ol.2014.1781.
 
30.  Yamashita N, Tokunaga E, Kitao H, Hisamats Y, Taketani K, Akiyoshi S, et al. Vimentin as a poor prognostic factor for triple-negative breast cancer. Cancer Res Clin Oncol. 2013;139:739-46. doi 10.1007/s00432-013-1376-6.
 
31.  Shibata K, Suzuki A, Watanabe T, Takasu N, Hirai I, Kimura W. ZEB-1 and E-cadherin expression may predict recurrence-free survival in patients with invasive ductal breast carcinoma. Yamagata Med J. 2015;33(2):61-9.
 
32.  LiZ, Yin S, Liu W, Zhang L, Chen B. Prognostic value of reduced E-cadherin expression in breast cancer: a meta-analysis. Oncotarget.  2017; 8:10, 16445-55.
 
33.  Wang J, Feng L, Zhu Z, Zheng, M, Wang D, Chen Z, et al. Aquaporins as diagnostic and therapeutic targets in cancer: How far we are? J Transl Med. 2015; 96:13-29.
 
34.  Kachroo P, Lee MH, Zhang L, Baratelli F, Lee G, Srivastava MK, et al. IL-27 inhibits epithelial-mesenchymal transition and angiogenic factor production in a STAT1-dominant pathway in human non-small cell lung cancer. J Exp Clin Cancer Res. 2013; 32:97. doi:10.1186/1756-9966-32-97.
 
35.  Tsubaki M, Komai M, Fujimoto S, Itoh T, Imano M, Sakamoto K, et al. Activation of NF-κB by the RANKL/RANK system up-regulates snail and twist expressions and induces epithelial-to-mesenchymal transition in mammary tumor cell lines. J Exp Clin Cancer Res. 2013;32:62. doi:10.1186/1756-9966-32-6.
 
1.      Ibrahim AS, Khaled HM, Mikhail NN, Baraka H, Kamel H. Cancer incidence in egypt: results of the national population-based cancer registry program. J Cancer Epidemiol. 2014;2014:437971. doi: 10.1155/2014/437971.
2.      Shibata K, Suzuki A, Watanabe T, Takasu N, Hirai L, Kimura W.ZEP-1 and E-cadherin expression may predict recurrence –free survival in patient with invasive ductal breast carcinoma. Yamagata Med J. 2015;33(2):61-69. doi: 10.150220003468.
3.    Benzina S, Beauregard AP, Guerrette R, Jean S, Faye MD, Laflamme M, et al. Pax-5 is a potent regulator of E-cadherin and breast cancer malignant processes. Oncotarget. 2017;8(7):12052-12066. doi: 10.18632/oncotarget.14511.
4.    Heerboth S, Housman G, Leary M, Longacre M, Byler S, Lapinska K, et al. EMT and tumor metastasis. Clin Transl Med. 2015;4:6. doi:10.1186/s40169-015-0048-3.
5.      Hegazy A. Clinical embryology for medical students and postgraduate doctors. Berlin: LAP ‘Lambert Academic Publishing’; 2014. 
6.      Huang X, Zhang C, Cai J, Shi G, Ke A, Dong Z, et al. Comprehensive multiple molecular profile of epithelial mesenchymal transition in intrahepatic cholangiocarcinoma patients. PLoS One. 2014; 9(5): e96860.
7.      Chen J, Wang T, Zhou YC, Gao F, Zhang ZH, Xu H, et al. Aquaporin 3 promotes epithelial-mesenchymal transition in gastric cancer.J Exp Clin Cancer Res. 2014;33:38. doi: 10.1186/1756-9966-33-38.
8.     Kang S, Chae YS, Lee SJ, Kang BW, Kim JG, Kim WW, et al. Aquaporin 3 Expression predicts survival in patients with HER2-positive early breast cancer. Anticancer Res. 2015;35(5):2775-82.
9.      Marlar S, Jensen HH, Login FH, Nejsum LN. Aquaporin-3 in Cancer. Int J Mol Sci. 2017;18(10). pii: E2106. doi: 10.3390/ijms18102106.
10.  Maitham AK, Luqmani YA.Role of aquaporins in breast cancer progression and metastasis. Chapter 4: Aquaporin-3 in cancer. 2016.p.59-83. Available at: http://dx.doi.org/10.5772/64446.
11.  Chen R, Shi Y, Amiduo R, Tuokan T, Suzuk L.Expression and prognostic value of aquaporin 1, 3 in cervical carcinoma in women of Uygur ethnicity from Xinjiang, China. PLoS One. 2014;9(6): e98576. doi:10.1371/journal. pone.0098576.
12.  Ji C, Cao C, Lu S, Kivlin R, Amaral A, Kouttab N, et al. Curcumin attenuates EGF-induced AQP3 up-regulation and cell migration in human ovarian cancer cells. Cancer Chemother Pharmacol. 2008;62(5):857-65. doi: 10.1007/s00280-007-0674-6.
13.  Hemalatha A, Suresh TN, Harendra Kumar ML. Expression of vimentin in breast carcinoma, its correlation with Ki67 and other histopathological parameters. Indian J Cancer. 2013;50:189-94
14.  Ricciardi GR, Adamo B, Ieni A, Licata L, Cardia R, Ferraro G, et al. Androgen receptor (AR), E-cadherin, and Ki-67 as emerging targets and novel prognostic markers in triple-negative breast cancer (TNBC) patients. PLoS One.  2015;10(6):e0128368.
15.  Abdelrahman AE, Arafa SA, Ahmed RA. Prognostic Value of twist-1, E-cadherin and EZH2 in prostate cancer: An immunohistochemical study. Turk Patoloji Derg. 2017;33(3):198-210 doi: 10.5146/tjpath.2016.01392.
16.  Ashaie MA, Chowdhury EH.Cadherins: the superfamily critically involved in breast cancer. Curr Pharm Des. 2016; 22:616-38
17.  Lakhani SR, Ellis IO, Schnitt SJ, Tan PH, van de Vijver MJ.WHO classification of tumors of the breast. 4th ed. Lyon, France: IARC Press; 2012.
18.  Edge SB, Byrd DR, Compton CC, Fritz AG, Greene FL, Trotti A. AJCC cancer staging manual, 7th ed. New York: Springer; 2010.
19.  Huang YT, Zhou J, Shi S, Xu HY, Qu F, Zhang D, et al. Identification of estrogen response element in aquaporin-3 gene that mediates estrogen-induced cell migration and invasion in estrogen receptor-positive breast cancer. Sci Rep. 2015; 5:12484.  doi: 10.1038/srep12484.
20.  Savagner P. The epithelial-mesenchymal transition (EMT) phenomenon. Ann Oncol. 2010;21 Suppl 7:vii89-92. doi: 10.1093/annonc/mdq292.
21.  Jeong H, Ryu YJ, An J, Lee Y, Kim A. Epithelial-mesenchymal transition in breast cancer correlates with high histological grade and triple-negative phenotype. Histopathology. 2012;60(6B):E87-95. doi:10.1111/j.1365-2559.2012.04195.x.
22.  Rodriguez-Pinilla SM, Sarrio D, Honrado E, Hardisson D, Calero F, et al.  Prognostic significance of basal-like phenotype and fascin expression in node-negative invasive breast carcinomas. Clin Cancer Res. 2006; 12: 1533–1539.
23.  Sarrió D, Rodriguez-Pinilla SM, Hardisson D, Cano A, Moreno-Bueno G, Palacios J. Epithelial-mesenchymal transition in breast cancer relates to the basal-like phenotype. Cancer Res. 2008;68(4):989-97. doi:10.1158/0008-5472.CAN-07-2017.
24.  Mendez MG, Kojima S, Goldman RD. Vimentin induces changes in cell shape, motility, and adhesion during the epithelial to mesenchymal transition. FASEB J. 2010;24(6):1838-51. doi: 10.1096/fj.09-151639.
25.  Neve RM, Chin K, Fridlyand J, Yeh J, Baehner FL, Fevr T, et al. A collection of breast cancer cell lines for the study of functionally distinct cancer subtypes. Cancer Cell. 2006;10(6):515-27.
26.  Hendrix MJ, Seftor EA, Seftor RE, Trevor KT. Experimental co-expression of vimentin and keratin intermediate filaments in human breast cancer cells results in phenotypic interconversion and increased invasive behavior. Am J Pathol. 1997;150(2):483-95.
27.  Vuoriluoto K, Haugen H, Kiviluoto S, Mpindi JP, Nevo J, Gjerdrum C, et al. Vimentin regulates EMT induction by Slug and oncogenic H-Ras and migration by governing Axl expression in breast cancer. Oncogene. 2011;30(12):1436-48. doi: 10.1038/onc.2010.509.
28.  Karihtala P, Auvinen P, Kauppila S, Haapasaari KM, Jukkola-Vuorinen A, Soini Y. Vimentin, zeb1 and Sip1 are up-regulated in triple-negative and basal-like breast cancers: association with an aggressive tumour phenotype. Breast Cancer Res Treat. 2013;138(1):81-90. doi: 10.1007/s10549-013-2442-0.
29.  Calaf G, Balajee AS, Montalvo-villagra MT, leon M, Navarrete MD, González alvarez R, et al. Vimentin and Notch as biomarkers for breast cancer progression. Oncol Lett. 2014; 7(3): 721-7. doi: 10.3892/ol.2014.1781.
30.  Yamashita N, Tokunaga E, Kitao H, Hisamats Y, Taketani K, Akiyoshi S, et al. Vimentin as a poor prognostic factor for triple-negative breast cancer. Cancer Res Clin Oncol. 2013;139:739-46. doi 10.1007/s00432-013-1376-6.
31.  Shibata K, Suzuki A, Watanabe T, Takasu N, Hirai I, Kimura W. ZEB-1 and E-cadherin expression may predict recurrence-free survival in patients with invasive ductal breast carcinoma. Yamagata Med J. 2015;33(2):61-9.
32.  LiZ, Yin S, Liu W, Zhang L, Chen B. Prognostic value of reduced E-cadherin expression in breast cancer: a meta-analysis. Oncotarget.  2017; 8:10, 16445-55.
33.  Wang J, Feng L, Zhu Z, Zheng, M, Wang D, Chen Z, et al. Aquaporins as diagnostic and therapeutic targets in cancer: How far we are? J Transl Med. 2015; 96:13-29.
34.  Kachroo P, Lee MH, Zhang L, Baratelli F, Lee G, Srivastava MK, et al. IL-27 inhibits epithelial-mesenchymal transition and angiogenic factor production in a STAT1-dominant pathway in human non-small cell lung cancer. J Exp Clin Cancer Res. 2013; 32:97. doi:10.1186/1756-9966-32-97.
35.  Tsubaki M, Komai M, Fujimoto S, Itoh T, Imano M, Sakamoto K, et al. Activation of NF-κB by the RANKL/RANK system up-regulates snail and twist expressions and induces epithelial-to-mesenchymal transition in mammary tumor cell lines. J Exp Clin Cancer Res. 2013;32:62. doi:10.1186/1756-9966-32-6.