Author(s)

Rui Wang

Affiliation(s)

Department of Pathology, Rizhao People's Hospital, Affiliated Jining Medical University, Rizhao, China

Corresponding Author

Rui Wang

ABSTRACT

Methods: Immunohistochemical Ultra Sensitive? S-P method was employed to detect the expression of Survivin and VEGF in 334 cases, including 60 cases of UDH, 57 cases of atypical ductal hyperplasia (ADH), 89 cases of ductal carcinoma in situ (DCIS), and 128 cases of invasive ductal carcinomas (IDC). Multiple biological parameters, including tumor size, grade, lymph node status, tumor metastasis, and stage, were compared to investigate the associations of Survivin and VEGF expressions in breast carcinoma. Results: (1) Survivin was mainly distributed in cytoplasm in UDH, but also distributed in nucleus and cytoplasm in IDC, DCIS, and ADH mammary tissues. (2) The positive rates of Survivin and VEGF in IDC were 67.2% and 68.8%, in DCIS were 59.6% and 44.9%, in ADH were 57.9% and 36.8%, and in UDH tissues were 1.7% and 20.0%. Compared with UDH tissues, there were significant differences in the positive rates of Survivin and VEGF in IDC (χ2=70.540, P=0.000; χ2=38.993, P=0.000), DCIS (χ2=51.967, P=0.000; χ2=9.815, P=0.002), and ADH (χ2=42.829, P=0.000; χ2=4.095, P=0.043), P<0.05, respectively. There were significant differences in the positive expression rates of VEGF between DCIS and IDC (χ2=12.298, P=0.001), and ADH and IDC (χ2=16.589, P=0.000); however, there were no significant differences in Survivin expression between IDC and DCIS (χ2=1.330, P=0.249), and IDC and ADH tissue (χ2=1.484, P=0.223). Positive expression rates of Survivin and VEGF showed no significant differences between ADH and DCIS tissue (χ2=0.039, P=0.843; χ2=0.938, P=0.333). (3) There was a positive correlation in over-expressions of Survivin and VEGF with histological grade (χ2=10.631, 12.412), lymph node metastasis (χ2=8.135, 7.677), distant metastasis (χ2=17.732, 7.621), and stage (χ2=6.992, 21.211) of IDC tumors. (4) The expression of VEGF was positively correlated with Survivin (r=0.211, P=0.017). Conclusion: The results demonstrate that the change in Survivin location from cytoplasm to nucleus might participate in oncogenesis and development of breast cancer. Over-expression of Survivin and VEGF might be important biological markers for invasion and metastasis of breast invasive carcinomas. Combined detection of Survivin and VEGF can serve as predictors for prognosis of breast carcinoma.

KEYWORDS

Breast cancer, Survivin, vascular endothelial growth factor, immunohistochemical, clinic, pathology

CITE THIS PAPER

Rui Wang. The clinical significance of survivin and vascular endothelial growth factor in breast cancer and precancerous lesions. Acta Translational Medicine. 2018, 1(1): 19-34.

REFERENCES

[1] Lakhani S.R., Ellis I.O., Schnitt S.J. WHO classification of tumours of the breast. Lyon, France: IARC Press, 1-117, 2012.
[2] Khan S., Ferguson B.H., Asuncion V.M.M. Localization and upregulation of survivin in cancer health disparities: a clinical perspective. Biologics: Targets and Therapy, 9(9): 57-67, 2015.
[3] Wang G., Qin Y., Zhang J., et al. Nipple Discharge of CA15-3, CA125, CEA and TSGF as a New Biomarker Panel for Breast Cancer. Int. J. Mol. Sci., 15: 9546-9565, 2014.
[4] Witteveen A., Kwast A.B., Sonke G.S. Survival after locoregional recurrence or second primary breast cancer: impact of the disease-free interval. PLoS One, 10(4): e0120832, 2015.
[5] Sueoka E., Sueoka-Aragane N., Sato A. Development of lymphoproliferative diseases by hypoxia inducible factor-1α is associated with prolonged lymphocyte survival. PLoS One, 8: e57833, 2013.
[6] Kopczyńska E., Makarewicz R. Endoglin—a marker of vascular endothelial cell proliferation in cancer. Wspolczesna Onkol, 16: 68-71, 2012.
[7] Kim M.J., Kim H.S., Lee S.H. NDRG2 controls COX-2/PGE2-mediated breast cancer cell migration and invasion. Mol Cells, 37(10): 759-765, 2014.
[8] Edge S.B., Byrd D.R., Compton C.C., eds. American Joint Committee on Cancer (AJCC) Cancer Staging Manual, 7th ed. New York, Springer, 2009.
[9] Sobin L.H., Gospodarowicz M.K., Wittekind Ch., eds. International Union Against Cancer (UICC): TNM classification of malignant tumors, 7th ed. Wiley-Blackwell, Oxford, 2009.
[10] Wang G., Zhang H., Zhang Z. Clinical and pathological characteristics of intraductal proliferative lesions coexisting with invasive ductal carcinomas. Chinese-German J Clin Oncol, 12: 574-580, 2013.
[11] Sueoka E., Sueoka-Aragane N., Sato A. Development of lymphoproliferative diseases by hypoxia inducible factor-1α is associated with prolonged lymphocyte survival. PLoS One, 8: e57833, 2013.
[12] Semenza G.L. Defining the role of Hypoxia inducible factor 1 in cancer biology and therapeutics. Oncogene, 29: 625-634, 2010.
[13] Dewi F.R., Fatchiyah F. Methylation impact analysis of erythropoietin (EPO) gene on hypoxia inducible factor-1α (HIF-1α) activity. Bioinformation, 9: 782-787, 2013.
[14] Liang Y., Li Z., Wang G. Expression of HIF-1α in breast cancer and precancerous lesions and the relationship to clinicopathological features. Chinese-German J Clin Oncol, 13: 23-28, 2014.
[15] Fortugno P., Wall N.R., Giodini A. Survivin exists in immunochemically distinct subcellular pools and is involved in spindle microtubule function. J Cell Sci., 115(Pt 3): 575-585, 2002.
[16] Church D.N., Talbot D.C. Survivin in solid tumors: rationale for development of inhibitors. Curr Oncol Rep., 14(2): 120-128, 2012.
[17] Simpson R.J., Lim J.W., Moritz R.L., Mathivanan S. Exosomes: proteomic insights and diagnostic potential. Expert Rev Proteomics, 6(3): 267-283, 2009.

[18] Greening D.W., Gopal S.K., Xu R., Simpson R.J., Chen W. Exosomes and their roles in immune regulation and cancer. Semin Cell Dev Biol, 40: 72-81, 2015.
[19] Khan S., Jutzy J.M., Aspe J.R., McGregor D.W., Neidigh J.W., Wall N.R. Survivin is released from cancer cells via exosomes. Apoptosis, 16(1): 1-12, 2011.
[20] Ale?kovi? M., Kang Y. Regulation of cancer metastasis by cell-free miRNAs. Biochim Biophys Acta, 1855(1): 24-42, 2015.
[21] Khan S., Jutzy J.M., Valenzuela M.M. Plasma-derived exosomal survivin, a plausible biomarker for early detection of prostate cancer. PLoS One, 7(10): e46737, 2012.
[22] Park J.O., Choi D.Y., Choi D.S. Identification and characterization of proteins isolated from microvesicles derived from human lung cancer pleural effusions. Proteomics, 13(14): 2125-2134, 2013.
[23] Shender V.O., Pavlyukov M.S., Ziganshin R.H. Proteome-metabolome profiling of ovarian cancer ascites reveals novel components involved in intercellular communication. Mol Cell Proteomics, 13(12): 3558-3571, 2014.
[24] Pietra G., Manzini C., Rivara S. Melanoma cells inhibit natural killer cell function by modulating the expression of activating receptors and cytolytic activity. Cancer Res, 72(6): 1407-1415, 2012.
[25] Jutzy J.M., Khan S., Asuncion-Valenzuela M.M., Milford T.A., Payne K.J., Wall N.R. Tumor-released survivin induces a type-2 T cell response and decreases cytotoxic T cell function in vitro. Cancer Microenviron, 6(1): 57-68, 2013.
[26] Dehal A., Abbas A., Johna S. Racial disparities in clinical presentation, surgical treatment and in-hospital outcomes of women with breast cancer: analysis of nationwide inpatient sample database. Breast Cancer Res Treat, 139(2): 561-569, 2013.
[27] Johnson R.H., Chien F.L., Bleyer A. Incidence of breast cancer with distant involvement among women in the United States, 1976 to 2009. JAMA, 309(8): 800-805, 2013.
[28] Adamkov M., Kajo K., Vybohova D., Krajcovic J., Stuller F., Rajcani J. Correlations of survivin expression with clinicomorphological parameters and hormonal receptor status in breast ductal carcinoma. Neoplasma, 59(1): 30-37, 2012.
[29] Rexhepaj E., Jirstrom K., O’Connor D.P. Validation of cytoplasmic-to-nuclear ratio of survivin as an indicator of improved prognosis in breast cancer. BMC Cancer, 10: 639, 2010.
[30] Dedi? Plaveti? N., Jaki?-Razumovi? J., Kuli? A., Vrbanec D. Prognostic value of proliferation markers expression in breast cancer. Med Oncol, 30(2): 523, 2013.
[31] Xu C., Yamamoto-Ibusuki M., Yamamoto Y. High survivin mRNA expression is a predictor of poor prognosis in breast cancer: a comparative study at the mRNA and protein level. Breast Cancer, 21(4): 482-490, 2014.
[32] Necochea-Campion R.D., Chen C.S., Mirshahidi S., Howard F.D., Wall N.R. Clinico-pathologic relevance of survivin splice variant expression in cancer. Cancer Lett, 339(2): 167-174, 2013.
[33] Thielemann A., Baszczuk A., Kopczyński Z. Clinical usefulness of assessing VEGF and soluble receptors sVEGFR-1 and sVEGFR-2 in women with breast cancer. Ann Agric Environ Med, 20: 293-297, 2013.
[34] Wang G.P., Qin M.H., Liang Y.A. The significance of biomarkers in nipple discharge and serum in diagnosis of breast cancer. In: Liquan Xie, Dianjian Huang, eds. Advanced Engineering and Technology. CRC Press, 665-671, 2014.
[35] Wang J.J., Sun X.C., Hu L. Endoglin (CD105) expression on microvessel endothelial cells in juvenile nasopharyngeal angiofibroma: tissue microarray analysis and association with prognostic significance. Head Neck, 35(12): 1719-1725, 2013.
[36] Koyama Y., Okayama H., Kumamoto K. Overexpression of endoglin (CD105) is associated with recurrence in radically resected gastric cancer. Experimental and Therapeutic Medicine, 1: 627-633, 2010.