Background: Triple-negative breast cancer (TNBC) is associated with characteristically poor prognosis. Tumor invasion and metastasis lead to high mortality of patients with breast cancer. The identification of biomarkers that allow early detection of metastasis is essential for therapeutic success in the treatment of breast cancer. This study aimed to asses the immune-histochemical expression of Rock-1 and claudin-4 in triple negative breast cancer and comparing them with classic prognostic parameters as age, grade, lymph node state, distant metastasis and stage to evaluate their prognostic significance in triple negative breast cancer. Material and methods: Forty cases of triple negative breast cancer were examined immunohistochemically using antibodies against claudin 4 and ROCK 1. Results: There was a difference in the expression of claudin 4 and Rock 1 among different clinicopathological parameters. A statistically significant relationship was found between high claudin 4 expression and higher age at time of diagnosis, advanced tumor stage, presence of distant metastasis and increased number of nodal involvement (p=0.041, 0.006, 0.001 and < 0.001 respectively). A highly statistically significant relationship was detected between high Rock 1 expression and increased number of nodal involvement (p <0.001). Also the expression of Rock 1 was different according to different age groups, tumor grades, tumor stages and presence or absence of distant metastasis but this difference was statistically insignificant (p=0.388, 0.602, 0.699 and 0. 944 respectively). Conclusion: our data suggest that claudin 4 and ROCK 1 are biomarkers of poor prognosis of patients with triple negative breast cancer.
Ola A. Harb,
Prognostic Implications of Claudin 4 and Rock 1 in Triple Negative Breast Cancer, Journal of Cancer Treatment and Research.
Vol. 5, No. 6,
2017, pp. 95-103.
Madhu Lal-Nag and Patrice J Morin; The claudins. Genome Biol. 2009, 10, 235. Published online 2009 Aug 26. doi:10.1186/gb-2009-10-8-23.
Lanigan F, McKiernan E, Brennan DJ, Hegarty S, Millikan RC, McBryan J, Jirstrom K, Landberg G, Martin F, Duffy MJ. Increased claudin-4 expression is associated with poor prognosis and high tumour grade in breast cancer Int J Cancer. 2009 May 1; 124(9).
Goldhirsch E. P, Winer A. S., Coates, R. D. Gelber, M. Piccart-Gebhart, B. Thürlimann, H.-J. Senn, Panel members, Kathy S. Albain, et al. (2013) Personalizing the treatment of women with early breast cancer: highlights of the St Gallen International Expert Consensus on the Primary Therapy of Early Breast Ann Oncol.; 24(9):2206-2223.
Won JR, Gao D, Chow C, et al. (2013) A survey of immunohistochemical biomarkers for basal-like breast can¬cer against a gene expression profile gold standard. Mod Pathol.; 26(11):1438-1450.
Kutomi, G. T. Ohmura, Y. Suzuki, (2012) “Clinico-pathological characteristics of basal type breast cancer in triple-negative breast cancer,” Journal of Cancer Therapy, vol. 3, pp. 836–840.
Györffy B, Lanczky A, Eklund AC, Denkert C, Budczies J, Li Q, et al. (2010). An online survival analysis tool to rapidly assess the effect of 22,277 genes on breast cancer prognosis using microarray data of 1,809 patients. Breast Cancer Res Treat.; 123:725–731.
Foulkes WD, Smith IE, Reis-Filho JS. (2010)Triple-negative breast cancer. N Engl J Med.; 363:1938–1948.
Fan J, Deng X, Gallagher JW, Huang H, Huang Y, Wen J, et al. (2012). Monitoring the progression of metastatic breast cancer on nanoporous silica chips. Philos Trans A: Math Phys Eng Sci; 370:2433–47.
Schackmann RC, Van Amersfoort M, Haarhuis JH, Vlug EJ, Halim VA, Roodhart JM, et al. (2011). Cytosolic p120-catenin regulates growth of metastatic lobular carcinoma through Rock 1-mediated anoikis resistance. J Clin Invest; 121:3176–88.
Singh A. B., Sharma A., Dhawan P. (2010). Claudin family of proteins and cancer: An overview. J. Oncol.; 2010:541957.
Ricardo S, Gerhard R, Cameselle-Teijeiro JF, Schmitt F, Paredes J. Claudin (2012). Expression in breast cancer: high or low, what to expect? Histol Histopathol. Oct; 27(10):1283-95.
Fielding CJ, Fielding PE: (2000). Cholesterol and caveolae: structural and funct ional relationships. Biochim Biophys Acta, 1529:210-22.
Guan R, Xu X, Chen M, Hu H, Ge H, Wen S, Zhou S, Pi R: (2013). Advances in the studies of roles of Rho/Rho-kinase in diseases and the development of its inhibitors. Eur J Med Chem, 70:613-622.
Lock FE, Ryan KR, Poulter NS, Parsons M, Hotchin NA: (2012). Differential regulation of adhesion complex turnover by ROCK 1 and ROCK 2. PLoS One, 7(2): e31423.
Liu X, Choy E, Hornicek FJ et al. (2012). ROCK 1 as a potential therapeutic target in osteosarcoma. J Orthop Res 2011; 29:1259–66.
Singh, A. B.; Sharma, A.; Dhawan, P. (2010). Claudin family of proteins and cancer: An overview. J. Oncol., 541957.
Zhu, Y.; Brannstrom, M.; Janson, P. O et al. (2006). Differences in expression patterns of the tight junction proteins, claudin 1, 3, 4 and 5, in human ovarian surface epithelium as compared to epithelia in inclusion cysts and epithelial ovarian tumours. Int. J Cancer, 118, 1884–1891.
Boireau, S.; Buchert, M.; Samuel, M. S.; Pannequin, J.; Ryan, J. L.; Choquet, A.; Avances, C.; Ernst, M.; et al. (2007). DNA-methylation-dependent alterations of claudin-4 expression in human bladder carcinoma. Carcinogenesis, 28, 246–258.
Tavassoli FA, Devilee P.; (2003). World Health Organization Classification of Tumors: Pathology and Genetics of Tumors of the Breast and Female Genital Organs. Lyon, France: IARC Press.
Greene FL, Pgae DL, Felming D, et al. (2002). American Joint Comettee on Cancer (AJCC) cancer staging manual. 6th ed. New York: Springer-Verlag.
Sheehan G M, Kallakury BV, Sheehan CE, Fisher HA, Kaufman Jr RP, Ross JS. (2007). Loss of claudins-1 and −7 and expression of claudins-3 and −4 correlate with prognostic variables in prostatic adenocarcinomas. Hum Pathol; 38:564–9.
Perou CM. (2010). Molecular stratification of triple-negative breast cancers. Oncologist.; 16:39-48.
Strehl J, Wachter D, Fasching P, et al. (2011). Invasive breast cancer: recognition of molecular subtypes. Breast Care; 6(4):256-264.
Zhang J, He X, Ma Y, Liu Y, Shi H, Guo W, Liu L. (2015). Overexpression of ROCK 1 and ROCK 2 inhibits human laryngeal squamous cell carcinoma. Int J Clin Exp Pathol; 8(1):244-251.
International Agency for Research Cancer (IARC). (2012). http://globocan.iarc.fr/facysheets/cancers/ breast.asp [accessed 03.19.12].
Fagan-Solis KD, Schneider SS, Pentecost BT, Bentley BA, Otis CN, Gierthy JF, et al. (2012). The ras homolog gene family, member A (Rho A) pathway mediates MMP-2 and MMP-9-independent invasive behavior in a triple-negative breast cancer cell line. J Cell Biochem; 114:1385–94.
Ortíz-López L, Morales-Mulia S, Ramírez-Rodríguez G, Benítez- King G. (2009). ROCK-regulated cytoskeletal dynamics participate in the inhibitory effect of melatonin on cancer cell migration. J Pineal Res; 46:15–21.
Tsukita S, Furuse M and Itoh M: (2001). Multifunctional strands in tight Junctions. Nat Rev Mol Cell Biol 2: 285-293.
Ivanov AI, Nusrat A and Parkos CA: (2004) Endocytosis of epithelial apical junctional proteins by a clathrin-mediated pathway into a unique storage compartment. Mol Biol Cell 15: 176-188.
Kominsky SL, Argani P, Korz D, Evron E, Raman V, Garrett E, Rein A, Sauter G, Kallioniemi OP and Sukumar S:(2003). Loss of the tight junction protein claudin-7 correlates with histological grade in both ductal carcinoma in situ and invasive ductal carcinoma of the breast. Oncogene 22: 2021-2033.
Sawada N, Murata M, Kikuchi K, Osanai M, Tobioka H, Kojima T and Chiba H: (2003). Tight junctions and human diseases. Med Electron Microsc 36: 147-156.
Hirohashi S and Kanai Y: (2003). Cell adhesion system and human cancer morphogenesis. Cancer Sci 94: 575-581.
Kulka J, Szasz AM, Nemeth Z, et al. (2009) Expression of tight junction protein claudin-4 in basal-like breast carcinomas. Pathol Oncol Res; 15:59–64 [PMID: 18752049.
Mona A. Abd-Elazeem, Marwa A. Abd-Elazeem, (2015). Claudin 4 expression in triple-negative breast cancer: correlation with androgen receptors and Ki-67 expression Annals of Diagnostic Pathology Volume 19, Issue 1, Pages 37–42.
Blanchard AA, Skliris GP, Watson PH, et al. (2009). Claudins-1, 3, and 4 protein expression in ER negative breast cancer correlates with markers of the basal phenotype. Virchows Arch; 454:647–56.
Toke´s AM, Kulka J, Paku S, et al. (2005). Claudin-1, −3 and −4 proteins and mRNA expression in benign and malignant breast lesions: a research study. Breast Cancer Res; 7: R 296–305.
Ricardo S, Gerhard R, Cameselle-Teijeiro JF, et al. (2012). Claudin expression in breast cancer: high or low, what to expect? Histol Histopathol; 27(10):1283–95.
Lanigan F, McKiernan E, Brennan DJ, et al. (2009). Increased claudin-4 expression is associated with poor prognosis and high tumor grade in breast cancer. Int J Cancer; 124:2088–97.
Garbar C, Dudez O, Mombelli S, et al. (2014). Claudin-4 Immunohistochemical Expression Is an Independent Prognosis Factor in Triple-negative Breast Cancers. J Multidiscip Pathol.; 1(1):1-10.
Kolokytha P, Yiannou P, Keramopoulos D, et al. (2014). Claudin-3 and claudin-4: distinct prognostic significance in triple-negative and luminal breast cancer. Appl Immunohistochem Mol Morphol; 22(2):125–31.
Narumiya S, Tanji M and Ishizaki T. (2009) Rho signaling, ROCK and mDia, in transformation, metastasis and invasion. Cancer Metastasis Rev; 28: 65-76.
Jaffe AB and Hall A. Rho GTPases: (2005). Biochemistry and biology. Annu Rev Cell Dev Biol; 21: 247-269.
Kamai T, Tsujii T, Arai K, Takagi K, Asami H, Ito Y and Oshima H. (2003). Significant association of Rho/ROCK pathway with invasion and metastasis of bladder cancer. Clin Cancer Res; 9: 2632-2641.
Wong CC, Wong CM, Tung EK, Man K and Ng IO. (2009). Rho-kinase 2 is frequently overexpressed in hepatocellular carcinoma and involved in tumor invasion. Hepatology; 49: 1583-1594.
Lane J, Martin TA, Watkins G, Mansel RE and Jiang WG. (2008). the expression and prognostic value of ROCK I and ROCK II and their role in human breast cancer. Int J Oncol; 33: 585-593.
Liu S, Goldstein RH, Scepansky EM, Rosenblatt M. (2009). Inhibition of rho- associated kinase signaling prevents breast cancer metastasis to human bone. Cancer Res; 69:8742–51.
Bottinoa J, Gelaleti GB, Maschioa LB Jardim-Perassia B V, Zuccaria DA. (2014). Immuno expression of ROCK-1 and MMP-9 as prognostic markers in breast cancer. Acta Histochemica 116 1367–1373.
Patel RA, Forinash KD, Pireddu R, Sun Y, Sun N, Martin MP, et al. (2012). RKI- 1447 is a potent inhibitor of the Rho-associated ROCK kinases with anti-invasive and antitumor activities in breast cancer. Cancer Res; 72:5025–34.
Lane J, Martin TA, Watkins G, Mansel RE, Jiang WG. (2008). The expression and prognostic value of ROCK I and ROCK II and their role in human breast cancer. Int J Oncol; 33:585–93.
Croft DR, Sahai E, Mavria G, Li S, Tsai J, Lee WM, et al. (2004). Conditional ROCK activation in vivo induces tumor cell dissemination and angiogenesis. Cancer Res; 64:8994–9001.