Skip to main content

Advertisement

SpringerLink
Log in

Estrogen Receptor β as a Prognostic Marker of Tumor Progression in Colorectal Cancer with Familial Adenomatous Polyposis and Sporadic Polyps

  • Original Article
  • Published:
Pathology & Oncology Research

Abstract

The incidence of colorectal cancer (CRC) is lower in women than in men, and sex steroids can be considered contributing factors because oral contraception usage and estrogen replacement therapy are associated with decreased risk. Conversely, colorectal polyp development in familial adenomatous polyposis (FAP) begins during puberty. The objectives were to evaluate the relationship between the expression of these hormone receptors and adenoma-carcinoma progression, CRC stage and overall survival. We studied 120 A.C. Camargo Cancer Center patients diagnosed with either FAP-associated or spontaneous adenomatous polyps or CRC to determine the immunohistochemical expression levels of estrogen receptor (ER)-α, ER-β and the progesterone and androgen receptors (480 analyses). The ER-β expression levels differed between the groups: the group with FAP polyps had lower ER-β expression than that of the sporadic polyp group. With transformation of the sporadic polyps to cancer, there was a considerable decrease in ER-β expression (from 90% with strong expression to 80% with absent or weak expression) (p < 0.001). The ER-β expression was lower in T3/T4 tumors than in T1/T2 tumors (p = 0.015). The 5-year overall survival of CRC patients positively expressing ER-β exceeded that of patients without detectable expression levels (74.8% vs. 44.3%, respectively; p = 0.035). There was no significant expression of the androgen or progesterone receptor or ER-α among the groups. Differences in ER-β expression represent a potential mechanism through which estrogen might alter the susceptibility to colon cancer, thereby confirming the possibility of a protective role of estrogen against colorectal carcinogenesis.

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

Access this article

Log in via an institution

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

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D (2011) Global cancer statistics. CA Cancer J Clin 61:69–90

    Article  PubMed  Google Scholar 

  2. Gebert JF, Dupon C, Kadmon M, Hahn M, Herfarth C, von Knebel DM, Schackert HK (1999) Combined molecular and clinical approaches for the identification of families with familial adenomatous polyposis coli. Ann Surg 229:350–361. doi:10.1097/00000658-199903000-00008

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  3. Goss KH, Groden J (2000) Biology of the adenomatous polyposis coli tumor suppressor. J Clin Oncol 18:1967–1979. doi:10.1200/JCO.2000.18.9.1967

    Article  PubMed  CAS  Google Scholar 

  4. Wong N, Lasko D, Rabelo R, Pinsky L, Gordon PH, Foulkes W (2001) Genetic counseling and interpretation of genetic tests in familial adenomatous polyposis and hereditary nonpolyposis colorectal cancer. Dis Colon rectum 44:271–279. doi:10.1007/BF02234304

  5. Vasen HF, Möslein G, Alonso A, Aretz S, Bernstein I, Bertario L, Blanco I, Bülow S, Burn J, Capella G, Colas C, Engel C, Frayling I, Friedl W, Hes FJ, Hodgson S, Järvinen H, Mecklin JP, Møller P, Myrhøi T, Nagengast FM, Parc Y, Phillips R, Clark SK, de Leon MP, Renkonen-Sinisalo L, Sampson JR, Stormorken A, Tejpar S, Thomas HJ, Wijnen J (2008) Guidelines for the clinical management of familial adenomatous polyposis (FAP). Gut 57:704–713. doi:10.1136/gut.2007.136127

    Article  PubMed  CAS  Google Scholar 

  6. Nieuwenhuis MH, Vasen HF (2007) Correlations between mutation site in APC and phenotype of familial adenomatous polyposis (FAP): a review of the literature. Crit Rev Oncol Hematol 61:153–161. doi:10.1016/j.critrevonc.2006.07.004

    Article  PubMed  CAS  Google Scholar 

  7. Kennelly R, Kavanagh DO, Hogan AM, Winter DC (2008) Oestrogen and the colon: potential mechanisms for cancer prevention. Lancet Oncol 9:385–391. doi:10.1016/S1470-2045(08)70100-1

    Article  PubMed  CAS  Google Scholar 

  8. Giardiello FM, Hylind LM, Trimbath JD, Hamilton SR, Romans KE, Cruz-Correa M, Corretti MC, Offerhaus JA, Yang VW (2005) Oral contraceptives and polyp regression in familial adenomatous polyposis. Gastroenterology 128:1077–1080

    Article  PubMed  Google Scholar 

  9. Chlebowski RT, Wactawski-Wende J, Ritenbaugh C, Hubbell FA, Ascensao J, Rodabough RJ, Rosenberg CA, Taylor VM, Harris R, Chen C, Adams-Campbell LL, White E, Investigators W's HI (2004) Estrogen plus progestin and colorectal cancer in postmenopausal women. N Engl J Med 350:991–1004. doi:10.1056/NEJMoa032071

    Article  PubMed  CAS  Google Scholar 

  10. Simon MS, Chlebowski RT, Wactawski-Wende J, Johnson KC, Muskovitz A, Kato I, Young A, Hubbell FA, Prentice RL (2012) Estrogen plus progestin and colorectal cancer incidence and mortality. J Clin Oncol 30:3983–3990. doi:10.1200/JCO.2012.42.7732

    Article  PubMed  PubMed Central  Google Scholar 

  11. Anderson GL, Limacher M, Assaf AR, Bassford T, Beresford SA, Black H, Bonds D, Brunner R, Brzyski R, Caan B, Chlebowski R, Curb D, Gass M, Hays J, Heiss G, Hendrix S, Howard BV, Hsia J, Hubbell A, Jackson R, Johnson KC, Judd H, Kotchen JM, Kuller L, LaCroix AZ, Lane D, Langer RD, Lasser N, Lewis CE, Manson J, Margolis K, Ockene J, O’Sullivan MJ, Phillips L, Prentice RL, Ritenbaugh C, Robbins J, Rossouw JE, Sarto G, Stefanick ML (2004) Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women's Health Initiative randomized controlled trial. JAMA 291:1701–1712. doi:10.1001/jama.291.14.1701

    Article  PubMed  CAS  Google Scholar 

  12. Rennert G, Rennert HS, Pinchev M, Lavie O, Gruber SB (2009) Use of hormone replacement therapy and the risk of colorectal cancer. J Clin Oncol 27:4542–4547. doi:10.1200/JCO.2009.22.0764

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  13. Green J, Czanner G, Reeves G, Watson J, Wise L, Roddam A, Beral V (2012) Menopausal hormone therapy and risk of gastrointestinal cancer: nested case-control study within a prospective cohort, and meta-analysis. Int J Cancer 130:2387–2396. doi:10.1002/ijc.26236

    Article  PubMed  CAS  Google Scholar 

  14. Lin KJ, Cheung WY, Lai JY, Giovannucci EL (2012) The effect of estrogen vs. combined estrogen-progestogen therapy on the risk of colorectal cancer. Int J Cancer 130:419–430. doi:10.1002/ijc.26026

    Article  PubMed  CAS  Google Scholar 

  15. Grodstein F, Newcomb PA, Stampfer MJ (1999) Postmenopausal hormone therapy and the risk of colorectal cancer: a review and meta-analysis. Am J Med 106:574–582. doi:10.1016/S0002-9343(99)00063-7

    Article  PubMed  CAS  Google Scholar 

  16. Kouzmenko AP, Takeyama K, Kawasaki Y, Akiyama T, Kato S (2008) Ligand-dependent interaction between estrogen receptor alpha and adenomatous polyposis coli. Genes Cells 13:723–730. doi:10.1111/j.1365-2443.2008.01200.x

    Article  PubMed  CAS  Google Scholar 

  17. Dawson PM, Shousha S, Blair SD, Carter GD, Jones J, Alaghband-Zadeh J, Theodorou NA (1990) Oestrogen receptors in colorectal carcinoma. J Clin Pathol 43:149–151. doi:10.1136/jcp.43.2.149

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  18. Hendrickse CW, Jones CE, Donovan IA, Neoptolemos JP, Baker PR (1993) Oestrogen and progesterone receptors in colorectal cancer and human colonic cancer cell lines. Br J Surg 80:636–640. doi:10.1002/bjs.1800800531

    Article  PubMed  CAS  Google Scholar 

  19. Di Leo A, Messa C, Russo F, Misciagna G, Guerra V, Taveri R, Leo S (1994) Prognostic value of cytosolic estrogen receptors in human colorectal carcinoma and surrounding mucosa. Preliminary results. Dig Dis Sci 39:2038–2042. doi:10.1007/BF02088144

    Article  PubMed  Google Scholar 

  20. Meggouh F, Lointier P, Pezet D, Saez S (1991) Status of sex steroid hormone receptors in large bowel cancer. Cancer 67:1964–1970. doi:10.1002/1097-0142(19910401)67:7<1964::AID-CNCR2820670724>3.0.CO;2-S

    Article  PubMed  CAS  Google Scholar 

  21. Slattery ML, Sweeney C, Murtaugh M, Ma KN, Caan BJ, Potter JD, Wolff R (2006) Associations between vitamin D, vitamin D receptor gene and the androgen receptor gene with colon and rectal cancer. Int J Cancer 118:3140–3146. doi:10.1002/ijc.21791

    Article  PubMed  CAS  Google Scholar 

  22. Slattery ML, Sweeney C, Murtaugh M, Ma KN, Wolff RK, Potter JD, Caan BJ, Samowitz W (2005) Associations between ERalpha, ERbeta, and AR genotypes and colon and rectal cancer. Cancer Epidemiol Biomark Prev 14:2936–2942. doi:10.1158/1055-9965.EPI-05-0514

    Article  CAS  Google Scholar 

  23. Mostafaie N, Kállay E, Sauerzapf E, Bonner E, Kriwanek S, Cross HS, Huber KR, Krugluger W (2009) Correlated downregulation of estrogen receptor beta and the circadian clock gene Per1 in human colorectal cancer. Mol Carcinog 48:642–647. doi:10.1002/mc.20510

    Article  PubMed  CAS  Google Scholar 

  24. Rüschoff J, Dietel M, Baretton G, Arbogast S, Walch A, Monges G, Chenard MP, Penault-Llorca F, Nagelmeier I, Schlake W, Höfler H, Kreipe HH (2010) HER2 diagnostics in gastric cancer-guideline validation and development of standardized immunohistochemical testing. Virchows Arch 457:299–307. doi:10.1007/s00428-010-0952-2

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  25. Foley EF, Jazaeri AA, Shupnik MA, Jazaeri O, Rice LW (2000) Selective loss of estrogen receptor beta in malignant human colon. Cancer Res 60:245–248

    PubMed  CAS  Google Scholar 

  26. Cho NL, Javid SH, Carothers AM, Redston M, Bertagnolli MM (2007) Estrogen receptors α and β are inhibitory modifiers of Apc-dependent tumorigenesis in the proximal colon of min/+ mice. Cancer Res 67:2366–2372. doi:10.1158/0008-5472.CAN-06-3026

    Article  PubMed  CAS  Google Scholar 

  27. Edge SB, Byrd DR, Compton CC, Fritz AG, Greene FL, Trotti A (2009) American joint committee on cancer staging manual, 7th edn. Springer, New York

    Google Scholar 

  28. Jassam N, Bell SM, Speirs V, Quirke P (2005) Loss of expression of oestrogen receptor beta in colon cancer and its association with dukes’ staging. Oncol Rep 14:17–21

    PubMed  CAS  Google Scholar 

  29. Konstantinopoulos PA, Kominea A, Vandoros G, Sykiotis GP, Andricopoulos P, Varakis I, Sotiropoulou-Bonikou G, Papavassiliou AG (2003) Oestrogen receptor beta (ERbeta) is abundantly expressed in normal colonic mucosa, but declines in colon adenocarcinoma paralleling the tumour’s dedifferentiation. Eur J Cancer 39:1251–1258. doi:10.1016/S0959-8049(03)00239-9

    Article  PubMed  CAS  Google Scholar 

  30. Jordan VC (2007) New insights into the metabolism of tamoxifen and its role in the treatment and prevention of breast cancer. Steroids 72:829–842. doi:10.1016/j.steroids.2007.07.009

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  31. Kato S, Sato T, Watanabe T, Takemasa S, Masuhiro Y, Ohtake F, Matsumoto T (2005) Function of nuclear sex hormone receptors in gene regulation. Cancer Chemother Pharmacol 56:4–9. doi:10.1007/s00280-005-0102-8

    Article  PubMed  CAS  Google Scholar 

  32. Ohtake F, Takeyama K, Matsumoto T, Kitagawa H, Yamamoto Y, Nohara K, Tohyama C, Krust A, Mimura J, Chambon P, Yanagisawa J, Fujii-Kuriyama Y, Kato S (2003) Modulation of oestrogen receptor signalling by association with the activated dioxin receptor. Nature 423:545–550. doi:10.1038/nature01606

    Article  PubMed  CAS  Google Scholar 

  33. Métivier R, Reid G, Gannon F (2006) Transcription in four dimensions: nuclear receptor-directed initiation of gene expression. EMBO Rep 7:161–167. doi:10.1038/sj.embor.7400626

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  34. Björnström L, Sjöberg M (2005) Mechanisms of estrogen receptor signaling: convergence of genomic and nongenomic actions on target genes. Mol Endocrinol 19:833–842. doi:10.1210/me.2004-0486

    Article  PubMed  CAS  Google Scholar 

  35. Vasudevan N, Pfaff DW (2007) Membrane-initiated actions of estrogens in neuroendocrinology: emerging principles. Endocr Rev 28:1–19. doi:10.1210/er.2005-0021

    Article  PubMed  CAS  Google Scholar 

  36. Nanda K, Bastian LA, Hasselblad V, Simel DL (1999) Hormone replacement therapy and the risk of colorectal cancer: a meta-analysis. Obstet Gynecol 93:880–888. doi:10.1016/S0029-7844(98)00424-4

    Article  PubMed  CAS  Google Scholar 

  37. Slattery ML, Potter JD, Curtin K, Edwards S, Ma KN, Anderson K, Schaffer D, Samowitz WS (2001) Estrogens reduce and withdrawal of estrogens increase risk of microsatellite instability-positive colon cancer. Cancer Res 61:126–130

    PubMed  CAS  Google Scholar 

Download references

Acknowledgments

We thank Dr. Renata Maymi Takahashi, Bruna Catin and Mariana Petaccia de Macedo, who was also a coworker in this study.

Author information

Authors and Affiliations

  1. Colorectal Tumor Nucleus of the Pelvic Surgery Department, A.C. Camargo Cancer Center, R. Professor Antônio Prudente, 211 Liberdade, São Paulo CEP, São Paulo, SP, 01509-010, Brazil

    Paulo Roberto Stevanato Filho, Samuel Aguiar Júnior, Fábio de Oliveira Ferreira, Wilson Toshihiko Nakagawa, Ranyell Matheus Sobreira Batista Spencer, Tiago Santoro Bezerra, Philip Edward Boggiss & Ademar Lopes

  2. Department of Pathology, A.C. Camargo Cancer Center, São Paulo, SP, Brazil

    Maria Dirlei Begnami

Authors
  1. Paulo Roberto Stevanato Filho
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Samuel Aguiar Júnior
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Maria Dirlei Begnami
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Fábio de Oliveira Ferreira
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Wilson Toshihiko Nakagawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Ranyell Matheus Sobreira Batista Spencer
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Tiago Santoro Bezerra
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Philip Edward Boggiss
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Ademar Lopes
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Paulo Roberto Stevanato Filho.

Ethics declarations

Grants

This study was supported by grants from the State of São Paulo Research Foundation (FAPESP - 1453/10 - http://www.fapesp.br/en). The funders had no role in the study design, data collection and analysis, decision to publish or preparation of the manuscript.

Conflict of Interest

The authors declare that there is no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Stevanato Filho, P.R., Aguiar Júnior, S., Begnami, M.D. et al. Estrogen Receptor β as a Prognostic Marker of Tumor Progression in Colorectal Cancer with Familial Adenomatous Polyposis and Sporadic Polyps. Pathol. Oncol. Res. 24, 533–540 (2018). https://doi.org/10.1007/s12253-017-0268-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12253-017-0268-5

Keywords

Search

Navigation