Skip to main content

Advertisement

SpringerLink
Log in

Increased risk for distant metastasis in patients with familial early-stage breast cancer and high EZH2 expression

  • Preclinical Study
  • Published:
Breast Cancer Research and Treatment Aims and scope Submit manuscript

Abstract

The identification of women with early-stage breast cancer who will develop distant metastasis may improve clinical management. The transcriptional regulator Enhancer of Zeste-2 (EZH2) is overexpressed in invasive breast carcinoma compared with benign breast tissues, with maximal expression in breast cancer metastasis. In this article, our purpose was to investigate the performance of EZH2 protein detection as a predictor of metastasis in women with early-stage breast cancer, which is unknown. We developed a cohort of 480 women with stage I–IIA breast cancer diagnosed between 1996 and 2002 and recorded detailed sociodemographic, clinical, and pathological information. Tumors were histologically characterized and arrayed in tissue microarrays containing 1,443 samples. The nuclear EZH2 expression was investigated by immunohistochemistry and was scored as 1–2 (negative and weak) or 3–4 (moderate and strong) using a validated scoring schema. Scores 1–2 were considered low EZH2; scores 3–4 were considered high EZH2. In this study, we found that after a median follow up of 9 years (range 0.04–14.5 years) 46 of 480 patients (9.6%) developed distant metastasis. High EZH2 was associated with larger size, high histological grade, negative hormone receptors, and first degree family history of breast and/or ovarian carcinoma. While EZH2 could not predict survival in the entire cohort, high EZH2 was a predictor of disease-specific survival in patients with early-stage disease and first degree family history (log rank P value 0.05). Importantly, in this group of patients, high EZH2 was an independent predictor of distant metastasis up to 15 years after primary carcinoma diagnosis (hazard ratio 6.58, 95% CI: 1.40–30.89, P = 0.016) providing survival information above and beyond currently used prognosticators. In conclusion, EZH2 may be a useful biomarker of long-term metastatic risk in women with familial early-stage breast cancer, and warrant further validation studies.

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

Similar content being viewed by others

References

  1. Sarrazin D, Dewar JA, Arriagada R et al (1986) Conservative management of breast cancer. Br J Surg 73:604–606

    Article  PubMed  CAS  Google Scholar 

  2. Llombart-Cussac A (2008) Improving decision-making in early breast cancer: who to treat and how? Breast Cancer Res Treat 112(Suppl 1):15–24

    Article  PubMed  Google Scholar 

  3. Laible G, Wolf A, Dorn R et al (1997) Mammalian homologues of the Polycomb-group gene Enhancer of zeste mediate gene silencing in Drosophila heterochromatin and at S. cerevisiae telomeres. EMBO J 16:3219–3232

    Article  PubMed  CAS  Google Scholar 

  4. Satijn DP, Otte AP (1999) Polycomb group protein complexes: do different complexes regulate distinct target genes? Biochim Biophys Acta 1447:1–16

    PubMed  CAS  Google Scholar 

  5. Ringrose L, Paro R (2004) Epigenetic regulation of cellular memory by the Polycomb and Trithorax group proteins. Annu Rev Genet 38:413–443

    Article  PubMed  CAS  Google Scholar 

  6. Haupt Y, Alexander WS, Barri G, Klinken SP, Adams JM (1991) Novel zinc finger gene implicated as myc collaborator by retrovirally accelerated lymphomagenesis in E mu-myc transgenic mice. Cell 65:753–763

    Article  PubMed  CAS  Google Scholar 

  7. Hess JL (2004) MLL: a histone methyltransferase disrupted in leukemia. Trends Mol Med 10:500–507

    Article  PubMed  CAS  Google Scholar 

  8. Boyer LA, Plath K, Zeitlinger J et al (2006) Polycomb complexes repress developmental regulators in murine embryonic stem cells. Nature 441:349–353

    Article  PubMed  CAS  Google Scholar 

  9. Levine SS, Weiss A, Erdjument-Bromage H, Shao Z, Tempst P, Kingston RE (2002) The core of the polycomb repressive complex is compositionally and functionally conserved in flies and humans. Mol Cell Biol 22:6070–6078

    Article  PubMed  CAS  Google Scholar 

  10. Gonzalez ME, Li X, Toy K et al (2009) Downregulation of EZH2 decreases growth of estrogen receptor-negative invasive breast carcinoma and requires BRCA1. Oncogene 28:843–853

    Article  PubMed  Google Scholar 

  11. Kleer CG, Cao Q, Varambally S et al (2003) EZH2 is a marker of aggressive breast cancer and promotes neoplastic transformation of breast epithelial cells. Proc Natl Acad Sci USA 100:11606–11611

    Article  PubMed  CAS  Google Scholar 

  12. Cao Q, Yu J, Dhanasekaran SM et al (2008) Repression of E-cadherin by the polycomb group protein EZH2 in cancer. Oncogene 27:7274–7284

    Article  PubMed  CAS  Google Scholar 

  13. Zeidler M, Varambally S, Cao Q et al (2005) The Polycomb group protein EZH2 impairs DNA repair in breast epithelial cells. Neoplasia 7:1011–1019

    Article  PubMed  CAS  Google Scholar 

  14. Chang CJ, Yang JY, Xia W et al (2011) EZH2 promotes expansion of breast tumor initiating cells through activation of RAF1-beta-catenin signaling. Cancer Cell 19:86–100

    Article  PubMed  CAS  Google Scholar 

  15. Gonzalez ME, DuPrie ML, Krueger H, Merajver SD, Ventura AC, Toy KA, Kleer CG (2011) Histone methyltransferase EZH2 induces Akt-dependent genomic instability and BRCA1 inhibition in breast cancer. Cancer Res 71:2360–2370

    Article  PubMed  CAS  Google Scholar 

  16. Bracken AP, Pasini D, Capra M, Prosperini E, Colli E, Helin K (2003) EZH2 is downstream of the pRB-E2F pathway, essential for proliferation and amplified in cancer. EMBO J 22:5323–5335

    Article  PubMed  CAS  Google Scholar 

  17. Bachmann IM, Halvorsen OJ, Collett K et al (2006) EZH2 expression is associated with high proliferation rate and aggressive tumor subgroups in cutaneous melanoma and cancers of the endometrium, prostate, and breast. J Clin Oncol 24:268–273

    Article  PubMed  CAS  Google Scholar 

  18. Collett K, Eide GE, Arnes J et al (2006) Expression of enhancer of zeste homologue 2 is significantly associated with increased tumor cell proliferation and is a marker of aggressive breast cancer. Clin Cancer Res 12:1168–1174

    Article  PubMed  CAS  Google Scholar 

  19. Raaphorst FM, Meijer CJ, Fieret E et al (2003) Poorly differentiated breast carcinoma is associated with increased expression of the human polycomb group EZH2 gene. Neoplasia 5:481–488

    PubMed  CAS  Google Scholar 

  20. Varambally S, Dhanasekaran SM, Zhou M et al (2002) The polycomb group protein EZH2 is involved in progression of prostate cancer. Nature 419:624–629

    Article  PubMed  CAS  Google Scholar 

  21. Gown AM (2008) Current issues in ER and HER2 testing by IHC in breast cancer. Mod Pathol 21(Suppl 2):S8–S15

    Article  PubMed  CAS  Google Scholar 

  22. McShane LM, Altman DG, Sauerbrei W, Taube SE, Gion M, Clark GM (2006) REporting recommendations for tumor MARKer prognostic studies (REMARK). Breast Cancer Res Treat 100:229–235

    Article  PubMed  Google Scholar 

  23. Ding L, Erdmann C, Chinnaiyan AM, Merajver SD, Kleer CG (2006) Identification of EZH2 as a molecular marker for a precancerous state in morphologically normal breast tissues. Cancer Res 66:4095–4099

    Article  PubMed  CAS  Google Scholar 

  24. Puppe J, Drost R, Liu X et al (2009) BRCA1-deficient mammary tumor cells are dependent on EZH2 expression and sensitive to Polycomb Repressive Complex 2-inhibitor 3-deazaneplanocin A. Breast Cancer 11:R63

    Article  Google Scholar 

  25. Chabner E, Nixon A, Gelman R et al (1998) Family history and treatment outcome in young women after breast-conserving surgery and radiation therapy for early-stage breast cancer. J Clin Oncol 16:2045–2051

    PubMed  CAS  Google Scholar 

  26. Ding L, Kleer CG (2006) Enhancer of Zeste 2 as a marker of preneoplastic progression in the breast. Cancer Res 66:9352–9355

    Article  PubMed  CAS  Google Scholar 

  27. Pietersen AM, Horlings HM, Hauptmann M et al (2008) EZH2 and BMI1 inversely correlate with prognosis and TP53 mutation in breast cancer. Breast Cancer 10:R109

    Article  Google Scholar 

  28. Arisan S, Buyuktuncer ED, Palavan-Unsal N, Caskurlu T, Cakir OO, Ergenekon E (2005) Increased expression of EZH2, a polycomb group protein, in bladder carcinoma. Urol Int 75:252–257

    Article  PubMed  CAS  Google Scholar 

  29. Raman JD, Mongan NP, Tickoo SK, Boorjian SA, Scherr DS, Gudas LJ (2005) Increased expression of the polycomb group gene, EZH2, in transitional cell carcinoma of the bladder. Clin Cancer Res 11:8570–8576

    Article  PubMed  CAS  Google Scholar 

  30. Weikert S, Christoph F, Kollermann J et al (2005) Expression levels of the EZH2 polycomb transcriptional repressor correlate with aggressiveness and invasive potential of bladder carcinomas. Int J Mol Med 16:349–353

    PubMed  CAS  Google Scholar 

  31. Matsukawa Y, Semba S, Kato H, Ito A, Yanagihara K, Yokozaki H (2006) Expression of the enhancer of zeste homolog 2 is correlated with poor prognosis in human gastric cancer. Cancer Sci 97:484–491

    Article  PubMed  CAS  Google Scholar 

  32. Breuer RH, Snijders PJ, Smit EF et al (2004) Increased expression of the EZH2 polycomb group gene in BMI-1-positive neoplastic cells during bronchial carcinogenesis. Neoplasia 6:736–743

    Article  PubMed  CAS  Google Scholar 

  33. Sudo T, Utsunomiya T, Mimori K et al (2005) Clinicopathological significance of EZH2 mRNA expression in patients with hepatocellular carcinoma. Br J Cancer 92:1754–1758

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

The authors thank Mrs. Robin Kunkel for artwork and Javed Siddiqui for his assistance with tissue microarray construction. This study was financially supported by the National Cancer Institute at the National Institutes of Health (R01 CA125577, UO1 CA154224, and 2R01 CA107469) to CGK; the Department of Defense Breast Cancer Research Program to SHA; the University of Michigan Comprehensive Cancer Center Core Grant (NIH/NCI 5 P30 CA46592); and the Josephine Ford Cancer Center.

Author information

Authors and Affiliations

  1. Department of Public Health Sciences, Henry Ford Hospital, Detroit, MI, USA

    Sharon Hensley Alford

  2. Department of Pathology, University of Michigan Medical School, 4217 Comprehensive Cancer Center, 1500 E. Medical Center Dr, Ann Arbor, MI, 48109, USA

    Katherine Toy & Celina G. Kleer

  3. Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI, USA

    Katherine Toy, Sofia D. Merajver & Celina G. Kleer

  4. Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA

    Sofia D. Merajver

Authors
  1. Sharon Hensley Alford
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Katherine Toy
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Sofia D. Merajver
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Celina G. Kleer
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Celina G. Kleer.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Alford, S.H., Toy, K., Merajver, S.D. et al. Increased risk for distant metastasis in patients with familial early-stage breast cancer and high EZH2 expression. Breast Cancer Res Treat 132, 429–437 (2012). https://doi.org/10.1007/s10549-011-1591-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10549-011-1591-2

Keywords

Search

Navigation