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Erschienen in: Breast Cancer 2/2019

12.09.2018 | Original Article

Expression of the RAC1, RHOA and CXCR4 proteins and their interaction as risk factors for infiltration to the nipple areola complex in operable breast carcinoma

verfasst von: Yusuf Heriady, Dimyati Achmad, Bethy S. Hernowo, Ahmad Faried, Darmadji Ismono, Dany Hilmanto

Erschienen in: Breast Cancer | Ausgabe 2/2019

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Abstract

Background

Nipple areola complex (NAC) infiltration in operable breast carcinoma (OBC) is associated with local recurrence. NAC infiltration in OBC suggests that RAC1, RHOA and CXCR4 proteins are risk factors for migration and infiltration of OBC to NAC. This study aims to analyze the expression and interactions of these proteins as risk factors for NAC infiltration in OBC.

Materials and methods

This is an analytic observational cross-sectional study coupled with a categorical comparative study in each 40 subjects of OBC with and without NAC infiltration. The immunohistochemistry performed with a cut-off point based on the result of a receiver operating characteristics (ROC).

Results

RAC1, p < 0.001 with POR 5.76, 95% CI: 2.06–16.08; RHOA, p < 0.001 with POR 7.00, 95% CI: 2.28–21.53; and CXCR4, p = 0.001 with POR 6.33, 95% CI 2.06–19.49. There was an interaction between RAC1 and RHOA (p < 0.001 with POR 17.14, 95% CI: 3.07-125.66); between RAC1 and CXCR4 (p < 0.001 with POR 30.93, 95% CI 3.62–686.89); between RHOA and CXCR4 (p < 0.001 with POR 10.21, 95% CI 2.19–54.17); and between the RAC1, RHOA and CXCR4 proteins (p < 0.001 with POR = 23.69, 95% CI 2.51–544.86).

Conclusion

We conclude that the expression of the RAC1, RHOA, and CXCR4 proteins and their interactions play a role as risk factors of NAC infiltration.
Literatur
1.
Zurück zum Zitat Lester SC. The breast. In: Kumar V, Abbas AK, Fausto N, Aster JC, editors. Robbins and Cotran pathologic basis of disease. 8th ed. Pennsylvania: Saunders; 2010. pp. 1065–95.CrossRef Lester SC. The breast. In: Kumar V, Abbas AK, Fausto N, Aster JC, editors. Robbins and Cotran pathologic basis of disease. 8th ed. Pennsylvania: Saunders; 2010. pp. 1065–95.CrossRef
4.
Zurück zum Zitat Profile of Disease Control and Environmental Health. Directorate general of disease control and environmental sanitation. South Jakarta: Indonesian Ministry of Health; 2007. pp 82–5. Profile of Disease Control and Environmental Health. Directorate general of disease control and environmental sanitation. South Jakarta: Indonesian Ministry of Health; 2007. pp 82–5.
5.
Zurück zum Zitat Schnelzer A, Prechtel D, Knaus U, Dehne K, Gerhard M, Graeff H, Harbeck N, Schmitt M, Lengyel E. Rac1 in human breast cancer: Overexpression, mutation analysis, and characterization of a new isoform, Rac1b. Oncogene. 2000;19:3013–20.CrossRefPubMed Schnelzer A, Prechtel D, Knaus U, Dehne K, Gerhard M, Graeff H, Harbeck N, Schmitt M, Lengyel E. Rac1 in human breast cancer: Overexpression, mutation analysis, and characterization of a new isoform, Rac1b. Oncogene. 2000;19:3013–20.CrossRefPubMed
6.
Zurück zum Zitat Müller A, Homey B, Soto H, Ge N, Catron D, Buchanan ME, McClanahan T, Murphy E, Yuan W, Wagner SN, Barrera JL, Mohar A, Verástegui E, Zlotnik A. Involvement of chemokine receptors in breast cancer metastasis. Nature. 2001;410:50–6.CrossRefPubMed Müller A, Homey B, Soto H, Ge N, Catron D, Buchanan ME, McClanahan T, Murphy E, Yuan W, Wagner SN, Barrera JL, Mohar A, Verástegui E, Zlotnik A. Involvement of chemokine receptors in breast cancer metastasis. Nature. 2001;410:50–6.CrossRefPubMed
7.
Zurück zum Zitat Ridley AJ. Rho GTPases and cell migration. J Cell Sci. 2001;114:2713–22.PubMed Ridley AJ. Rho GTPases and cell migration. J Cell Sci. 2001;114:2713–22.PubMed
8.
Zurück zum Zitat Friedl P, Wolf K. Tumour-cell invasion and migration: diversity and escape mechanisms. Nat Rev Cancer. 2003;3:362–74.CrossRefPubMed Friedl P, Wolf K. Tumour-cell invasion and migration: diversity and escape mechanisms. Nat Rev Cancer. 2003;3:362–74.CrossRefPubMed
9.
Zurück zum Zitat Schioppa T, Uranchimeg B, Saccani A, Biswas SK, Doni A, Rapisarda A, Bernasconi S, Saccani S, Nebuloni M, Vago L, Mantovani A, Melillo G, Sica A. Regulation of the chemokine receptor CXCR4 by hypoxia. J Exp Med. 2003;198:1391–402.CrossRefPubMedPubMedCentral Schioppa T, Uranchimeg B, Saccani A, Biswas SK, Doni A, Rapisarda A, Bernasconi S, Saccani S, Nebuloni M, Vago L, Mantovani A, Melillo G, Sica A. Regulation of the chemokine receptor CXCR4 by hypoxia. J Exp Med. 2003;198:1391–402.CrossRefPubMedPubMedCentral
12.
Zurück zum Zitat McCarty KS Jr, Miller LS, Cox EB, Konrath J, McCarty KS Sr. Estrogen receptor analyses. Correlation of biochemical and immunohistochemical methods using monoclonal antireceptor antibodies. Arch Pathol Lab Med. 1985;109:716–21.PubMed McCarty KS Jr, Miller LS, Cox EB, Konrath J, McCarty KS Sr. Estrogen receptor analyses. Correlation of biochemical and immunohistochemical methods using monoclonal antireceptor antibodies. Arch Pathol Lab Med. 1985;109:716–21.PubMed
13.
Zurück zum Zitat Garcia-Etienne CA, Borgen PI. Update on the indications for nipple-sparing mastectomy. J Support Oncol. 2006;4:225–30.PubMed Garcia-Etienne CA, Borgen PI. Update on the indications for nipple-sparing mastectomy. J Support Oncol. 2006;4:225–30.PubMed
14.
Zurück zum Zitat Laronga C, Kemp B, Johnston D, Robb GL, Singletary SE. The incidence of occult nipple-areola complex involvement in breast cancer patients receiving a skin-sparing mastectomy. Ann Surg Oncol. 1999;6:609–13.CrossRefPubMed Laronga C, Kemp B, Johnston D, Robb GL, Singletary SE. The incidence of occult nipple-areola complex involvement in breast cancer patients receiving a skin-sparing mastectomy. Ann Surg Oncol. 1999;6:609–13.CrossRefPubMed
15.
Zurück zum Zitat Simmons RM, Brennan M, Christos P, King V, Osborne M. Analysis of nipple/ areolar involvement with mastectomy: can the areola be preserved? Ann Surg Oncol. 2002;9:165–8.CrossRefPubMed Simmons RM, Brennan M, Christos P, King V, Osborne M. Analysis of nipple/ areolar involvement with mastectomy: can the areola be preserved? Ann Surg Oncol. 2002;9:165–8.CrossRefPubMed
16.
Zurück zum Zitat Lambert PA, Kolm P, Perry RR. Parameters that predict nipple involvement in breast cancer. J Am Coll Surg. 2000;191:354–9.CrossRefPubMed Lambert PA, Kolm P, Perry RR. Parameters that predict nipple involvement in breast cancer. J Am Coll Surg. 2000;191:354–9.CrossRefPubMed
17.
Zurück zum Zitat Vyas JJ, Chinoy RF, Vaidya JS. Prediction of nipple and areola involvement in breast cancer. Eur J Surg Oncol. 1998;24:15–6.CrossRefPubMed Vyas JJ, Chinoy RF, Vaidya JS. Prediction of nipple and areola involvement in breast cancer. Eur J Surg Oncol. 1998;24:15–6.CrossRefPubMed
18.
Zurück zum Zitat Cojoc M, Peitzsch C, Trautmann F, Polishchuk L, Telegeev GD, Dubrovska A. Emerging targets in cancer management: role of the CXCL12/CXCR4 axis. Onco Targets Ther. 2013;6:1347–61.PubMedPubMedCentral Cojoc M, Peitzsch C, Trautmann F, Polishchuk L, Telegeev GD, Dubrovska A. Emerging targets in cancer management: role of the CXCL12/CXCR4 axis. Onco Targets Ther. 2013;6:1347–61.PubMedPubMedCentral
19.
Zurück zum Zitat Engers R, Ziegler S, Mueller M, Walter A, Willers R, Gabbert HE. Prognostic relevance of increased Rac GTPase expression in prostate carcinomas. Endocr Relat Cancer. 2007;14:245–56.CrossRefPubMed Engers R, Ziegler S, Mueller M, Walter A, Willers R, Gabbert HE. Prognostic relevance of increased Rac GTPase expression in prostate carcinomas. Endocr Relat Cancer. 2007;14:245–56.CrossRefPubMed
20.
Zurück zum Zitat Baugher PJ, Krishnamoorthy L, Price JE, Dharmawardhane SF. Rac1 and Rac3 isoform activation is involved in the invasive and metastatic phenotype of human breast cancer cells. Breast Cancer Res. 2005;7:R965-74.CrossRefPubMed Baugher PJ, Krishnamoorthy L, Price JE, Dharmawardhane SF. Rac1 and Rac3 isoform activation is involved in the invasive and metastatic phenotype of human breast cancer cells. Breast Cancer Res. 2005;7:R965-74.CrossRefPubMed
21.
Zurück zum Zitat Lozano E, Betson M, Braga VM. Tumor progression: Small GTPases and loss of cell-cell adhesion. Bioessays. 2003;25:452–63.CrossRefPubMed Lozano E, Betson M, Braga VM. Tumor progression: Small GTPases and loss of cell-cell adhesion. Bioessays. 2003;25:452–63.CrossRefPubMed
22.
Zurück zum Zitat Besson A, Assoian RK, Roberts JM. Regulation of the cytoskeleton: an oncogenic function for CDK inhibitors? Nat Rev Cancer. 2004;4:948–55.CrossRefPubMed Besson A, Assoian RK, Roberts JM. Regulation of the cytoskeleton: an oncogenic function for CDK inhibitors? Nat Rev Cancer. 2004;4:948–55.CrossRefPubMed
23.
Zurück zum Zitat Fritz G, Just I, Kaina B. Rho GTPases are over-expressed in human tumors. Int J Cancer. 1999;81:682–7.CrossRefPubMed Fritz G, Just I, Kaina B. Rho GTPases are over-expressed in human tumors. Int J Cancer. 1999;81:682–7.CrossRefPubMed
24.
Zurück zum Zitat Bellizzi A, Mangia A, Chiriatti A, Petroni S, Quaranta M, Schittulli F, Malfettone A, Cardone RA, Paradiso A, Reshkin SJ. RhoA protein expression in primary breast cancers and matched lymphocytes is associated with progression of the disease. Int J Mol Med. 2008;22:25–31.PubMed Bellizzi A, Mangia A, Chiriatti A, Petroni S, Quaranta M, Schittulli F, Malfettone A, Cardone RA, Paradiso A, Reshkin SJ. RhoA protein expression in primary breast cancers and matched lymphocytes is associated with progression of the disease. Int J Mol Med. 2008;22:25–31.PubMed
25.
Zurück zum Zitat Taniguchi K, Tsujitani S, Tokuyasu N, Naka T, Tatebe S, Kondo A, Ikeguchi M. Rho-ROCK expression predicts the prognosis in patients with T3/T4 gastric cancer. Yonago Acta Med. 2007;50:9–15. Taniguchi K, Tsujitani S, Tokuyasu N, Naka T, Tatebe S, Kondo A, Ikeguchi M. Rho-ROCK expression predicts the prognosis in patients with T3/T4 gastric cancer. Yonago Acta Med. 2007;50:9–15.
26.
Zurück zum Zitat Pu YS, Wang CW, Liu GY, Kuo YZ, Huang CY, Kang WY, Shun CT, Lin CC, Wu WJ, Hour TC. Down regulated expression of RhoA in human conventional renal cell carcinoma. Anticancer Res. 2008;28:2039–44.PubMed Pu YS, Wang CW, Liu GY, Kuo YZ, Huang CY, Kang WY, Shun CT, Lin CC, Wu WJ, Hour TC. Down regulated expression of RhoA in human conventional renal cell carcinoma. Anticancer Res. 2008;28:2039–44.PubMed
27.
Zurück zum Zitat Vega FM, Fruhwirth G, Tony NG, Ridley AJ. RhoA and RhoC have distinct roles in migration and invasion by acting through different targets. J Cell Biol. 2011;193:655–65.CrossRefPubMedPubMedCentral Vega FM, Fruhwirth G, Tony NG, Ridley AJ. RhoA and RhoC have distinct roles in migration and invasion by acting through different targets. J Cell Biol. 2011;193:655–65.CrossRefPubMedPubMedCentral
28.
Zurück zum Zitat O’Connor KL, Min Chen M. Dynamic functions of RhoA in tumor cell migration and invasion. Small GTPases. 2013;4:1–7.CrossRef O’Connor KL, Min Chen M. Dynamic functions of RhoA in tumor cell migration and invasion. Small GTPases. 2013;4:1–7.CrossRef
29.
Zurück zum Zitat Mukherjee D, Zhao J. The role of chemokine receptor CXCR4 in breast cancer metastasis. Am J Cancer Res. 2013;3:46–57.PubMedPubMedCentral Mukherjee D, Zhao J. The role of chemokine receptor CXCR4 in breast cancer metastasis. Am J Cancer Res. 2013;3:46–57.PubMedPubMedCentral
30.
Zurück zum Zitat Wang L, Chen W, Gao L, Yang Q, Liu B, Wu Z, Wang Y, Sun Y. High expression of CXCR4, CXCR7 and SDF-1 predicts poor survival in renal cell carcinoma. World J Surg Oncol. 2012;10:212.CrossRefPubMedPubMedCentral Wang L, Chen W, Gao L, Yang Q, Liu B, Wu Z, Wang Y, Sun Y. High expression of CXCR4, CXCR7 and SDF-1 predicts poor survival in renal cell carcinoma. World J Surg Oncol. 2012;10:212.CrossRefPubMedPubMedCentral
31.
Zurück zum Zitat Li N, Guo W, Shi J, Xue J, Hu H, Xie D, Wu M, Cheng S. Expression of the chemokine receptor CXCR4 in human hepatocellular carcinoma and its role in portal vein tumor thrombus. J Exp Clin Cancer Res. 2010;29:156.CrossRefPubMedPubMedCentral Li N, Guo W, Shi J, Xue J, Hu H, Xie D, Wu M, Cheng S. Expression of the chemokine receptor CXCR4 in human hepatocellular carcinoma and its role in portal vein tumor thrombus. J Exp Clin Cancer Res. 2010;29:156.CrossRefPubMedPubMedCentral
32.
Zurück zum Zitat Kodama J, Hasengaowa, Kusumoto T, Seki N, Matsuo T, Ojima Y, Nakamura K, Hongo A, Hiramatsu Y. Association of CXCR4 and CCR7 chemokine receptor expression and lymph node metastasis in human cervical cancer. Ann Oncol. 2007;18:70–6.CrossRefPubMed Kodama J, Hasengaowa, Kusumoto T, Seki N, Matsuo T, Ojima Y, Nakamura K, Hongo A, Hiramatsu Y. Association of CXCR4 and CCR7 chemokine receptor expression and lymph node metastasis in human cervical cancer. Ann Oncol. 2007;18:70–6.CrossRefPubMed
Metadaten
Titel
Expression of the RAC1, RHOA and CXCR4 proteins and their interaction as risk factors for infiltration to the nipple areola complex in operable breast carcinoma
verfasst von
Yusuf Heriady
Dimyati Achmad
Bethy S. Hernowo
Ahmad Faried
Darmadji Ismono
Dany Hilmanto
Publikationsdatum
12.09.2018
Verlag
Springer Japan
Erschienen in
Breast Cancer / Ausgabe 2/2019
Print ISSN: 1340-6868
Elektronische ISSN: 1880-4233
DOI
https://doi.org/10.1007/s12282-018-0907-z

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