Skip to main content
Log in

The expression of estrogen receptors β2, 5 identifies and is associated with Prognosis in non-small cell lung cancer

  • Original Article
  • Published:
Endocrine Aims and scope Submit manuscript

Abstract

Estrogens play a pivotal role in the development and progression of non-small lung cancer (NSCLC). With the discovery of estrogen receptor β (ERβ) isoforms, some controversial roles of ERβ were explained adequately in NSCLC. In this study, our aim is to elucidate expression, distribution, and prognostic significance of ERβ 1, 2, 5 in NSCLC. Estrogen receptors β1, 2, 5 protein expression were confirmed by Western-blot analysis in all frozen tissues, and immunohistochemistry (IHC). Nuclear and cytoplasmic staining was evaluated and correlated with histopathologic characteristics, overall survival (OS) and disease-free survival (DFS) via Pearson χ 2 square, Kaplan–Meier plots and Cox proportional hazard models. ERβ1 was commonly found in the cytoplasm and was the most abundant isofroms followed by ERβ2 and ERβ5 which were localized in the cytoplasm and nucleus. In contrast to BPL, both in nucleus and cytoplasm, ERβ1, ERβ2, and ERβ5 were over expressed all in NSCLC (P < 0.05). IHC results were correlated with pathological and clinical follow-up data to delineate the distinct roles of ERβ1, ERβ2, and ERβ5 in NSCLC. nERβ1 “nuclear”, cERβ2 and cERβ5 “cytoplasm” were in a negative correlation with the pathological stage and lymph node metastasis. In a Kaplan–Meier analysis, the expression cERβ2 and cERβ5 identified a group of patients with the longest DFS and OS. Cox proportional hazard models revealed that cERβ2 and cERβ5 predicted long time to DFS and OS. This is the first study to uncover the expression of ERβ1, ERβ2, and ERβ5, and show that they were over expressed in NSCLC. Meantime, we find that positive expression of cERβ2 and cERβ5 were in a positive correlation with DFS, and have prognostic values for the progression of NSCLC.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. R.J. Pietras, D.C. Marquez, H.W. Chen et al., Estrogen and growth factor receptor interactions in human breast and non-small cell lung cancer cells. Steroids 70(5–7), 372–381 (2005)

    Article  PubMed  CAS  Google Scholar 

  2. H. Kawasaki, D.C. Altieri, C.D. Lu et al., Inhibition of apoptosis by surviving predicts shorter survival rates in colorectal cancer. Cancer Res. 58(22), 5071–5074 (1998)

    PubMed  CAS  Google Scholar 

  3. X.R. Yang, R.M. Pfeiffer, M. Garcia-Closas et al., Hormonal markers in breast cancer: co-expression, relationship with pathologic characteristics, and risk factor associations in a population-based study. Cancer Res. 67(21), 10608–10617 (2007)

    Article  PubMed  CAS  Google Scholar 

  4. C.I. Henschke, R. Yip, O.S. Miettinen, Women’s susceptibility to tobacco carcinogens and survival after diagnosis of lung cancer. JAMA 296(2), 180–184 (2006)

    Article  PubMed  Google Scholar 

  5. L.P. Stabile, A.L. Davis, C.T. Gubish et al., Human non-small cell lung tumors and cells derived from normal lung express both estrogen receptor alpha and beta and show biological responses to estrogen. Cancer Res. 62(7), 2141–2150 (2002)

    PubMed  CAS  Google Scholar 

  6. H. Niikawa, T. Suzuki, Y. Miki et al., Intratumoral estrogens and estrogen receptors in human non-small cell lung carcinoma. Clin. Cancer Res. 14(14), 4417–4426 (2008)

    Article  PubMed  CAS  Google Scholar 

  7. P.A. Hershberger, A.C. Vasquez, B. Kanterewicz et al., Regulation of endogenous gene expression in human non-small cell lung cancer cells by estrogen receptor ligands. Cancer Res. 65(4), 1598–1605 (2005)

    Article  PubMed  CAS  Google Scholar 

  8. Z. Hammoud, B. Tan, S. Badve et al., Estrogen promotes tumor progression in a genetically defined mouse model of lung adenocarcinoma. Endocr. Relat. Cancer 15(2), 475–483 (2008)

    Article  PubMed  CAS  Google Scholar 

  9. J.T. Moore, D.D. McKee, K. Slentz-Kesler et al., Cloning and characterization of human estrogen receptor beta isoforms. Biochem. Biophys. Res. Commun. 247(1), 75–78 (1998)

    Article  PubMed  CAS  Google Scholar 

  10. A.M. Shaaban, A.R. Green, S. Karthik, Nuclear and cytoplasmic expression of ERbeta1, ERbeta2, and ERbeta5 identifies distinct prognostic outcome for breast cancer patients. Clin. Cancer Res. 14(16), 5228–5235 (2008)

    Article  PubMed  CAS  Google Scholar 

  11. M. Yan, M. Rayoo, E.A. Takano et al., Nuclear and cytoplasmic expressions of ERbeta1 and ERbeta2 are predictive of response to therapy and alters prognosis in familial breast cancers. Breast Cancer Res Treat. 126(2), 395–405 (2011). doi:10.1007/s10549-010-0941-9

    Article  PubMed  CAS  Google Scholar 

  12. A. Chi et al., Differential expression of estrogen receptor beta isoforms in human breast cancer tissue. Anticancer Res. 23(1A), 211–216 (2003)

    PubMed  CAS  Google Scholar 

  13. Y.K. Leung et al., Estrogen receptor beta2 and beta5 are associated with poor prognosis in prostate cancer, and promote cancer cell migration and invasion. Endocr. Relat. Cancer 17(3), 675–689 (2010)

    Article  PubMed  CAS  Google Scholar 

  14. G. Zhao, S. Zhao, T. Wang et al., Estrogen receptor β signaling regulates the progression of Chinese non-small cell lung cancer. J. Steroid Biochem. Mol. Biol. 1(22), 47–57 (2011). doi:10.1016/j.jsbmb.2011.01.006

    Article  Google Scholar 

  15. H. Niikawa, T. Suzuki, Y. Miki et al., Intratumoral estrogens and estrogen receptors in human non-small cell lung carcinoma. Clin. Cancer Res. 14(14), 4417–4426 (2008)

    Article  PubMed  CAS  Google Scholar 

  16. B.G. Skov, B.M. Fischer, H. Pappot, Oestrogen receptor beta over expression in males with non-small cell lung cancer is associated with better survival. Lung Cancer 59(1), 88–94 (2008)

    Article  PubMed  Google Scholar 

  17. H. Kawai et al., Estrogen receptor alpha and beta are prognostic factors in non-small cell lung cancer. Clin. Cancer Res. 11(14), 5084–5089 (2005)

    Article  PubMed  CAS  Google Scholar 

  18. M.D. Mamoun Younes, M.D. Naoko Honma, Estrogen receptorβ. Arch. Pathol. Lab. Med. 135, 63–66 (2011)

    PubMed  Google Scholar 

  19. G. Zhang, X. Liu, A.M. Farkas et al., Estrogen receptor beta functions through nongenomic mechanisms in lung cancer cells. Mol. Endocrinol. 23(2), 146–156 (2009)

    Article  PubMed  Google Scholar 

  20. H. Niikawa, T. Suzuki, Y. Miki et al., Intratumoral estrogens and estrogen receptors in human non-small cell lung carcinoma. Clin. Cancer Res. 14(14), 4417–4426 (2008)

    Article  PubMed  CAS  Google Scholar 

  21. O. Wada-Hiraike, O. Imamov, H. Hiraike, K. Hultenby, T. Schwend, Y. Omoto, M. Warner, J. Gustafsson, A. Proc. Natl. Acad. Sci. USA 103, 2959–2964 (2006)

    Article  CAS  Google Scholar 

  22. C.C. Weige, K.F. Allred, C. Allred, Estradiol alters cell growth in nonmalignant colonocytes and reduces the formation of preneoplastic lesions in the colon. D. Cancer Res. 69, 9118–9124 (2009)

    Article  CAS  Google Scholar 

  23. P.A. Hershberger, A.C. Vasquez, B. Kanterewicz et al., Regulation of endogenous gene expression in human non-small cell lung cancer cells by estrogen receptor ligands. Cancer Res. 65(4), 1598–1605 (2005)

    Article  PubMed  CAS  Google Scholar 

  24. C.T. Wu, Y.L. Chang, J.Y. Shih, Y.C. Lee, The significance of estrogen receptor beta in 301 surgically treated non-small cell lung cancers. J. Thorac. Cardiovasc. Surg. 130(4), 979–986 (2005)

    Article  PubMed  CAS  Google Scholar 

  25. P.A. Hershberger, L.P. Stabile, B. Kanterewicz et al., Estrogen receptor beta (ERbeta) subtype-specific ligands increase transcription, p44/p42 mitogen activated protein kinase (MAPK) activation and growth in human non-small cell lung cancer cells. J. Steroid Biochem. Mol. Biol. 116(1–2), 102–109 (2009)

    Article  PubMed  CAS  Google Scholar 

  26. R.J. Pietras, D.C. Márquez-Garbán, Membrane-associated estrogen receptor signaling pathways in human cancers. Clin. Cancer Res. 13(16), 4672–4676 (2007)

    Article  PubMed  CAS  Google Scholar 

  27. C. Zhao, K. Dahlman-Wright, J.-Å. Gustafsson, Estrogen signaling via estrogen receptor β. JBC 285(51), 39575–39579 (2010). doi:10.1074/jbc.R110.180109

    Article  CAS  Google Scholar 

  28. L. Bjornstrom, M. Sjoberg, Mechanisms of estrogen receptor signaling: convergence of genomic and non-genomic actions on target genes. Mol. Endocrinol. 19, 833–842 (2005)

    Article  PubMed  Google Scholar 

  29. A. Jemal, R. Siegel, E. Ward et al., Cancer statistics, 2009. CA Cancer J. Clin. 59(4), 225–249 (2009)

    Article  PubMed  Google Scholar 

  30. P.R. Cammarata, J. Flynn, S. Gottipati, S. Chu et al., Differential expression and comparative subcellular localization of estrogen receptor beta isoforms in virally transformed and normal cultured human lens epithelial cells. Exp. Eye Res. 81, 165–175 (2005)

    Article  PubMed  CAS  Google Scholar 

  31. A. Pedram, M. Razandi, D.C. Wallace et al., Functional estrogen receptors in the mitochondria of breast cancer cells. Mol. Biol. Cell 17, 2125–2137 (2006)

    Article  PubMed  CAS  Google Scholar 

  32. Jose Russo, Jin-Qiang Chen, Patricia A. Russo et al., ERβ shift from mitochondria to nucleus during estrogen-induced neoplastic transformation of human breast epithelial cells and is involved in estrogen-induced synthesis of mitochondrial respiratory chain proteins. Mol. Cell Res. 12, 1732–1746 (2007)

    Google Scholar 

  33. D. Menendez, A. Inga, M.A. Resnich et al., Estrogen receptor acting in cis enhances WT and mutant p53 transactivation at canonical and noncanonical p53 target sequences. Proc. Natl. Acad. Sci. USA 107, 1500–1505 (2010)

    Article  PubMed  CAS  Google Scholar 

  34. S. Kousteni et al., Nongenotropic, sex-nonspecific signaling through the estrogen or androgen receptors: dissociation from transcriptional activity. Cell 104, 719–730 (2001)

    PubMed  CAS  Google Scholar 

  35. C. Thomas et al., The different roles of ER subtype in cancer biology and therapy. Nat. Rev. Cancer 11, 597–608 (2011)

    Article  PubMed  CAS  Google Scholar 

  36. Chunyan Zhao, Jason Matthews, Michel Tujague et al., Estrogen receptor β2 negatively regulates the transactivation of Estrogen receptor alpha in human breast cancer cells. Cancer Res. 67(8), 3955–3962 (2007)

    Article  PubMed  CAS  Google Scholar 

  37. T. Simoncini, A. Hafezi-Moghadam, D.P. Brazil et al., Interaction of estrogen receptor with the regulatory subunit of phosphatidylinositol-3-OH kinase. Nature 407, 538–541 (2007)

    Google Scholar 

  38. P.A. Hershberger, A.C. Vasquez, B. Kanterewicz, S. Land, J.M. Siegfried, M. Nichols, Regulation of endogenous gene expression in human non-small cell lung cancer cells by estrogen receptor ligands. Cancer Res. 65(4), 1598–1605 (2005)

    Article  PubMed  CAS  Google Scholar 

  39. Y.-K. Leung, P. Mak et al., Estrogen receptor (ER)-β isoforms: a key to understanding ER-β signaling. PNAS 103(35), 13162–13167 (2006)

    Article  PubMed  CAS  Google Scholar 

  40. H. Kawasaki, D.C. Altieri et al., Inhibition of apoptosis by surviving predicts shorter survival rates in colorectal cancer. J Cancer Res. 58(22), 5071–5074 (1998)

    CAS  Google Scholar 

  41. X.R. Yang, R.M.P. Feiffer et al., Hormonal markers in breast cancer: coexpression, relationship with pathologic characteristics, and risk factor associations in a population-based study. J. Cancer Res. 67(21), 10608–10617 (2007)

    Article  CAS  Google Scholar 

  42. P.J. Carder, C. Murphy, P. Dervan et al., A multi-centre investigation towards reaching a consensus on the immunohistochemical detection of ERβ in archival formalin-fixed paraffin embedded human breast tissue. Breast Cancer Res. Treat. 92, 287–293 (2005)

    Article  PubMed  Google Scholar 

Download references

Conflict of interest

All authors declare that: we have no proprietary, financial, professional or other personal interest of any nature or kind in any product, service and/or company that could be construed as influencing the position presented in.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Yongde Liao.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Liu, Z., Liao, Y., Tang, H. et al. The expression of estrogen receptors β2, 5 identifies and is associated with Prognosis in non-small cell lung cancer. Endocrine 44, 517–524 (2013). https://doi.org/10.1007/s12020-013-9916-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12020-013-9916-z

Keywords

Navigation