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HtrA3 is negatively correlated with lymph node metastasis in invasive ductal breast cancer

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Tumor Biology

Abstract

Breast cancer is the most common cancer in women worldwide. Studies have shown that the high temperature requirement factor A3 (HtrA3) is involved in important physiological processes including maintenance of mitochondrial homeostasis, cell death, and cell signaling. HtrA3 is reported to be downregulated in several cancers and has been correlated with advancing cancer stage. We performed a retrospective study using our breast cancer tissue bank to investigate whether the expression of HtrA3 correlated with lymphatic metastasis in breast cancer and whether the expression of HtrA3 was correlated with estrogen receptor (ER) and progesterone receptor (PR) expression in breast cancer. Breast cancer tissues from 156 invasive ductal breast cancer patients with or without lymphatic metastasis were collected and the levels of HtrA3 were measured by immunohistochemistry and western blotting. The expression of HtrA3 was lower in breast cancer. In particular, HtrA3 expression in breast cancer with lymphatic metastasis was lower than that in breast cancer without lymphatic metastasis. In breast cancers with no lymphatic metastasis, the expression of HtrA3 was lower in patients with ER- and PR-positive tumors, but when breast cancers with lymphatic metastasis were analyzed, there was no difference in HtrA3 expression between ER- and PR-positive or ER- and PR-negative tumors. These data suggest that the expression of HtrA3 was negatively correlated with lymphatic metastasis in breast cancer but not correlated with ER and PR positivity or negativity. A better understanding of the mechanism of HtrA3 may provide the basis for future development of a novel therapeutic target in breast cancer.

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References

  1. Ferlay J, Shin HR, Bray F, et al. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer. 2010;127:2893–917.

    Article  PubMed  CAS  Google Scholar 

  2. Gonzalez-Angulo AM, Morales-Vasquez F, Hortobagyi GN. Overview of resistance to systemic therapy in patients with breast cancer. Adv Exp Med Biol. 2007;608:1–22.

    Article  PubMed  CAS  Google Scholar 

  3. Donegan WL. Tumor-related prognostic factors for breast cancer. CA Cancer J Clin. 1997;47:28–51.

    Article  PubMed  CAS  Google Scholar 

  4. Fisher ER, Kotwal N, Hermann C, et al. Types of tumor lymphoid response and sinus histiocytosis. Relationship to five-year, disease-free survival in patients with breast cancer. Arch Pathol Lab Med. 1983;107:222–7.

    PubMed  CAS  Google Scholar 

  5. Clausen T, Southan C, Ehrmann M. The HtrA family of proteases: implications for protein composition and cell fate. Mol Cell. 2002;10:443–55.

    Article  PubMed  CAS  Google Scholar 

  6. Zurawa-Janicka D, Skorko-Glonek J, Lipinska B. HtrA proteins as targets in therapy of cancer and other diseases. Expert Opin Ther Targets. 2010;14:665–79.

    Article  PubMed  CAS  Google Scholar 

  7. Clausen T, Kaiser M, Huber R, et al. HTRA proteases: regulated proteolysis in protein quality control. Nat Rev Mol Cell Biol. 2011;12:152–62.

    Article  PubMed  CAS  Google Scholar 

  8. Chien J, Campioni M, Shridhar V, Baldi A. HtrA serine proteases as potential therapeutic targets in cancer. Curr Cancer Drug Targets. 2009;9:451–68.

    Article  PubMed  CAS  Google Scholar 

  9. Nie G, Li Y, Hale K, et al. Serine peptidase HTRA3 is closely associated with human placental development and is elevated in pregnancy serum. Biol Reprod. 2006;74:366–74.

    Article  PubMed  CAS  Google Scholar 

  10. Nie GY, Hampton A, Li Y, et al. Identification and cloning of two isoforms of human high-temperature requirement factor A3 (HtrA3), characterization of its genomic structure and comparison of its tissue distribution with HtrA1 and HtrA2. Biochem J. 2003;371:39–48.

    Article  PubMed  CAS  Google Scholar 

  11. Nie GY, Li Y, Minoura H, et al. A novel serine protease of the mammalian HtrA family is up-regulated in mouse uterus coinciding with placentation. Mol Hum Reprod. 2003;9:279–90.

    Article  PubMed  CAS  Google Scholar 

  12. Beleford D, Liu Z, Rattan R, et al. Methylation induced gene silencing of HtrA3 in smoking-related lung cancer. Clin Cancer Res. 2010;16:398–409.

    Article  PubMed  CAS  Google Scholar 

  13. Beleford D, Rattan R, Chien J, et al. High temperature requirement A3 (HtrA3) promotes etoposide- and cisplatin-induced cytotoxicity in lung cancer cell lines. J Biol Chem. 2010;285:12011–27.

    Article  PubMed  CAS  Google Scholar 

  14. Bowden MA, Di Nezza-Cossens LA, Jobling T, et al. Serine proteases HTRA1 and HTRA3 are down-regulated with increasing grades of human endometrial cancer. Gynecol Oncol. 2006;103:253–60.

    Article  PubMed  CAS  Google Scholar 

  15. Narkiewicz J, Klasa-Mazurkiewicz D, Zurawa-Janicka D, et al. Changes in mRNA and protein levels of human HtrA1, HtrA2 and HtrA3 in ovarian cancer. Clin Biochem. 2008;41:561–9.

    Article  PubMed  CAS  Google Scholar 

  16. Narkiewicz J, Lapinska-Szumczyk S, Zurawa-Janicka D, et al. Expression of human HtrA1, HtrA2, HtrA3 and TGF-beta1 genes in primary endometrial cancer. Oncol Rep. 2009;21:1529–37.

    PubMed  CAS  Google Scholar 

  17. Singh HL, Fuller PJ, Harrison C, et al. HtrA3 is downregulated in cancer cell lines and significantly reduced in primary serous and granulosa cell ovarian tumors. J Cancer. 2013;4(2):152–64.

    Article  PubMed  CAS  Google Scholar 

  18. de Boer M, van Deurzen CH, van Dijck JA, et al. Micrometastases or isolated tumor cells and the outcome of breast cancer. N Engl J Med. 2009;361:653–63.

    Article  PubMed  Google Scholar 

  19. Neuhausen SL, Brummel S, Ding YC, et al. Genetic variation in IGF2 and HTRA1 and breast cancer risk among BRCA1 and BRCA2 carriers. Cancer Epidemiol Biomarkers Prev. 2011;20:1690–702.

    Article  PubMed  CAS  Google Scholar 

  20. Chien J, Staub J, Hu SI, et al. A candidate tumor suppressor HtrA1 is downregulated in ovarian cancer. Oncogene. 2004;23:1636–44.

    Article  PubMed  CAS  Google Scholar 

  21. Zumbrunn J, Trueb B. Primary structure of a putative serine protease specific for IGF-binding proteins. FEBS Lett. 1996;398:187–92.

    Article  PubMed  CAS  Google Scholar 

  22. Hammond ME, Hayes DF, Wolff AC, et al. American Society of Clinical Oncology/College of American Pathologists guideline recommendations for immunohistochemical testing of estrogen and progesterone receptors in breast cancer. J Oncol Pract. 2010;6:195–7.

    Article  PubMed  Google Scholar 

  23. Dynon K, Heng S, Puryer M, et al. HtrA3 as an early marker for preeclampsia: specific monoclonal antibodies and sensitive high-throughput assays for serum screening. PLoS One. 2012;7:e45956.

    Article  PubMed  CAS  Google Scholar 

  24. Soslow RA, Dannenberg AJ, Rush D, et al. COX-2 is expressed in human pulmonary, colonic, and mammary tumors. Cancer. 2000;89:2637–45.

    Article  PubMed  CAS  Google Scholar 

  25. Society AC. Cancer facts and figures. Atlanta: Society AC; 2010.

  26. Baldi A, De Luca A, Morini M, et al. The HtrA1 serine protease is down-regulated during human melanoma progression and represses growth of metastatic melanoma cells. Oncogene. 2002;21:6684–8.

    Article  PubMed  CAS  Google Scholar 

  27. Tocharus J, Tsuchiya A, Kajikawa M, et al. Developmentally regulated expression of mouse HtrA3 and its role as an inhibitor of TGF-beta signaling. Dev Growth Differ. 2004;46:257–74.

    Article  PubMed  CAS  Google Scholar 

  28. Dumont N, Arteaga CL. Targeting the TGF beta signaling network in human neoplasia. Cancer Cell. 2003;3:531–6.

    Article  PubMed  CAS  Google Scholar 

  29. Singh H, Endo Y, Nie G. Decidual HtrA3 negatively regulates trophoblast invasion during human placentation. Hum Reprod. 2011;26:748–57.

    Article  PubMed  CAS  Google Scholar 

  30. Singh H, Makino SI, Endo Y, et al. Inhibition of HTRA3 stimulates trophoblast invasion during human placental development. Placenta. 2010;31:1085–92.

    Article  PubMed  CAS  Google Scholar 

  31. Amir E, Seruga B, Serrano R, et al. Targeting DNA repair in breast cancer: a clinical and translational update. Cancer Treat Rev. 2010;36:557–65.

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

This study was supported by the Chinese National Nature Sciences Foundation (grant number 81100437 to M Zhao) and Australian National and Health and Medical Research Council (Senior Research Fellowship GNT1041835 to G Nie). Authors thank all the women who donated tissues for this study. The authors also thank Dr. Joanna James from The University of Auckland for reviewing this manuscript.

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Authors and Affiliations

  1. Wuxi Maternity and Children Health Hospital Affiliated Nanjing Medical University, No 48 Huaishu Street, Wuxi, Jiangsu, China

    Yongxiang Yin, Man Wu, Min Zhao & Qi Chen

  2. Prince Henry’s Institute of Medical Research, Melbourne, Australia

    Guiying Nie

  3. Department of Biochemistry, Monash University, Melbourne, Australia

    Guiying Nie

  4. Jiangsu Institute of Nuclear Medicine, Wuxi, China

    Ke Wang

  5. Department of Obstetrics and Gynaecology, The University of Auckland, Auckland, New Zealand

    Jia Wei

Authors
  1. Yongxiang Yin
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  2. Man Wu
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  3. Guiying Nie
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  4. Ke Wang
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  5. Jia Wei
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  6. Min Zhao
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  7. Qi Chen
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Corresponding author

Correspondence to Min Zhao.

Additional information

Drs. Y Yin and M Wu equally contributed to this work.

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Yin, Y., Wu, M., Nie, G. et al. HtrA3 is negatively correlated with lymph node metastasis in invasive ductal breast cancer. Tumor Biol. 34, 3611–3617 (2013). https://doi.org/10.1007/s13277-013-0942-5

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  • DOI: https://doi.org/10.1007/s13277-013-0942-5

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