Journal of Breast Cancer

Korean Breast Cancer Society (한국유방암학회)
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STAT3, a Poor Survival Predicator, Is Associated with Lymph Node Metastasis from Breast Cancer

Chen, Yujuan;Wang, Jing;Wang, Xiaodong;Liu, Xuejuan;Li, Hongjiang;Lv, Qing;Zhu, Jingqiang;Wei, Bing;Tang, Ying

  • Published : 20130300
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Abstract

Purpose: The aim of this study is to explore signal transducer and activator of transcription 3 (STAT3) expression in breast cancer and to analyze the detailed mechanism that STAT3 contributes to the progression of breast cancer. Methods: We retrospectively analyzed the clinicopathologic characteristics and overall survival (OS) of 140 breast cancer patients after curative surgery, and detected STAT3 expression, phosphorylated STAT3 (pSTAT3) expression, Ki-67 expression, vascular endothelial growth factor (VEGF)-C and -D expression in breast cancer tissues, and adjacent nontumor tissues. Survival analysis and relationship analysis were adopted for demonstrated the important mechanism of STAT3 contribution to progression of breast cancer. Results: STAT3 expression, pSTAT3 expression, Ki-67 expression, VEGF-C expression, and VEGF-D expression in breast cancer tissues were significantly higher than those in adjacent nontumor tissues, respectively. With survival analysis, only number of lymph node metastasis (N stage) was identified as the independent predictors of the OS of breast cancer patients. Besides, we demonstrated there was the most prominent correlation between STAT3 expression and lymph node metastasis in breast cancer tissues by using the multinominal regression method. Conclusion: STAT3, a poor survival biomarker potential association with lymph node metastasis, was suitable for predication the OS of breast cancer patients after curative resection.

Keywords

References

  1. Cowin P, Welch DR. Breast cancer progression: controversies and consensus in the molecular mechanisms of metastasis and EMT. J Mammary Gland Biol Neoplasia 2007;12:99-102. https://doi.org/10.1007/s10911-007-9041-9
  2. Naik AM, Fey J, Gemignani M, Heerdt A, Montgomery L, Petrek J, et al. The risk of axillary relapse after sentinel lymph node biopsy for breast cancer is comparable with that of axillary lymph node dissection: a follow-up study of 4008 procedures. Ann Surg 2004;240:462-8. https://doi.org/10.1097/01.sla.0000137130.23530.19
  3. Sola M, Alberro JA, Fraile M, Santesteban P, Ramos M, Fabregas R, et al. Complete axillary lymph node dissection versus clinical follow-up in breast cancer patients with sentinel node micrometastasis: final results from the multicenter clinical trial AATRM 048/13/2000. Ann Surg Oncol 2013;20:120-7. https://doi.org/10.1245/s10434-012-2569-y
  4. Sanuki N, Takeda A, Amemiya A, Ofuchi T, Ono M, Ogata H, et al. Outcomes of clinically node-negative breast cancer without axillary dissection: can preserved axilla be safely treated with radiation after a positive sentinel node biopsy? Clin Breast Cancer 2013;13:69-76. https://doi.org/10.1016/j.clbc.2012.09.005
  5. Noguchi M, Morioka E, Ohno Y, Nakano Y, Kosaka T. The changing role of axillary lymph node dissection for breast cancer. Breast Cancer 2013;20:41-6. https://doi.org/10.1007/s12282-012-0416-4
  6. Park J, Fey JV, Naik AM, Borgen PI, Van Zee KJ, Cody HS 3rd. A declining rate of completion axillary dissection in sentinel lymph node-positive breast cancer patients is associated with the use of a multivariate nomogram. Ann Surg 2007; 245:462-468. https://doi.org/10.1097/01.sla.0000250439.86020.85
  7. Glechner A, Wöckel A, Gartlehner G, Thaler K, Strobelberger M, Griebler U, et al. Sentinel lymph node dissection only versus complete axillary lymph node dissection in early invasive breast cancer: a systematic review and meta-analysis. Eur J Cancer. Epub 2012 Oct 17. DOI: http://dx.doi.org/10.1016/j.ejca.2012.09.010.
  8. Mandriota SJ, Jussila L, Jeltsch M, Compagni A, Baetens D, Prevo R, et al. Vascular endothelial growth factor-C-mediated lymphangiogenesis promotes tumour metastasis. EMBO J 2001;20:672-82. https://doi.org/10.1093/emboj/20.4.672
  9. Van Trappen PO, Steele D, Lowe DG, Baithun S, Beasley N, Thiele W, et al. Expression of vascular endothelial growth factor (VEGF)-C and VEGF-D, and their receptor VEGFR-3, during different stages of cervical carcinogenesis. J Pathol 2003;201:544-54. https://doi.org/10.1002/path.1467
  10. Couto JP, Daly L, Almeida A, Knauf JA, Fagin JA, Sobrinho-Simoes M, et al. STAT3 negatively regulates thyroid tumorigenesis. Proc Natl Acad Sci U S A 2012;109:E2361-70. https://doi.org/10.1073/pnas.1201232109
  11. Amin HM, McDonnell TJ, Ma Y, Lin Q, Fujio Y, Kunisada K, et al. Selective inhibition of STAT3 induces apoptosis and G(1) cell cycle arrest in ALK-positive anaplastic large cell lymphoma. Oncogene 2004;23: 5426-34. https://doi.org/10.1038/sj.onc.1207703
  12. Zhang F, Li C, Halfter H, Liu J. Delineating an oncostatin M-activated STAT3 signaling pathway that coordinates the expression of genes involved in cell cycle regulation and extracellular matrix deposition of MCF-7 cells. Oncogene 2003;22:894-905. https://doi.org/10.1038/sj.onc.1206158
  13. Niu G, Wright KL, Huang M, Song L, Haura E, Turkson J, et al. Constitutive Stat3 activity up-regulates VEGF expression and tumor angiogenesis. Oncogene 2002;21:2000-8. https://doi.org/10.1038/sj.onc.1205260
  14. Messina JL, Yu H, Riker AI, Munster PN, Jove RL, Daud AI. Activated stat-3 in melanoma. Cancer Control 2008;15:196-201. https://doi.org/10.1177/107327480801500302
  15. Zhao X, Sun X, Li XL. Expression and clinical significance of STAT3, P-STAT3, and VEGF-C in small cell lung cancer. Asian Pac J Cancer Prev 2012;13:2873-7. https://doi.org/10.7314/APJCP.2012.13.6.2873
  16. Cai QW, Li J, Li XQ, Wang JQ, Huang Y. Expression of STAT3, MMP-1 and TIMP-1 in gastric cancer and correlation with pathological features. Mol Med Report 2012;5:1438-42.
  17. Jiang R, Jin Z, Liu Z, Sun L, Wang L, Li K. Correlation of activated STAT3 expression with clinicopathologic features in lung adenocarcinoma and squamous cell carcinoma. Mol Diagn Ther 2011;15:347-52. https://doi.org/10.1007/BF03256470
  18. Deng JY, Sun D, Liu XY, Pan Y, Liang H. STAT-3 correlates with lymph node metastasis and cell survival in gastric cancer. World J Gastroenterol 2010;16:5380-7. https://doi.org/10.3748/wjg.v16.i42.5380
  19. Takemoto S, Ushijima K, Kawano K, Yamaguchi T, Terada A, Fujiyoshi N, et al. Expression of activated signal transducer and activator of transcription-3 predicts poor prognosis in cervical squamous-cell carcinoma. Br J Cancer 2009;101:967-72. https://doi.org/10.1038/sj.bjc.6605212
  20. Fidler IJ. The pathogenesis of cancer metastasis: the 'seed and soil' hypothesis revisited. Nat Rev Cancer 2003;3:453-8. https://doi.org/10.1038/nrc1098
  21. Kim T, Giuliano AE, Lyman GH. Lymphatic mapping and sentinel lymph node biopsy in early-stage breast carcinoma: a metaanalysis. Cancer 2006;106:4-16. https://doi.org/10.1002/cncr.21568
  22. Hatake K, Tokudome N, Ito Y. Next generation molecular targeted agents for breast cancer: focus on EGFR and VEGFR pathways. Breast Cancer 2007;14:132-49. https://doi.org/10.2325/jbcs.977
  23. Yue P, Zhang X, Paladino D, Sengupta B, Ahmad S, Holloway RW, et al. Hyperactive EGF receptor, Jaks and Stat3 signaling promote enhanced colony-forming ability, motility and migration of cisplatin-resistant ovarian cancer cells. Oncogene 2012;31:2309-22. https://doi.org/10.1038/onc.2011.409
  24. Pytowski B, Goldman J, Persaud K, Wu Y, Witte L, Hicklin DJ, et al. Complete and specific inhibition of adult lymphatic regeneration by a novel VEGFR-3 neutralizing antibody. J Natl Cancer Inst 2005;97:14-21. https://doi.org/10.1093/jnci/dji003
  25. Schoppmann SF, Jesch B, Friedrich J, Jomrich G, Maroske F, Birner P. Phosphorylation of signal transducer and activator of transcription 3 (STAT3) correlates with Her-2 status, carbonic anhydrase 9 expression and prognosis in esophageal cancer. Clin Exp Metastasis 2012;29:615-24. https://doi.org/10.1007/s10585-012-9475-3
  26. Kim HS, Park YH, Lee J, Ahn JS, Kim J, Shim YM, et al. Clinical impact of phosphorylated signal transducer and activator of transcription 3, epidermal growth factor receptor, p53, and vascular endothelial growth factor receptor 1 expression in resected adenocarcinoma of lung by using tissue microarray. Cancer 2010;116:676-85. https://doi.org/10.1002/cncr.24748
  27. Shah NG, Trivedi TI, Tankshali RA, Goswami JV, Jetly DH, Shukla SN, et al. Prognostic significance of molecular markers in oral squamous cell carcinoma: a multivariate analysis. Head Neck 2009;31:1544-56. https://doi.org/10.1002/hed.21126

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