Breast Cancer Research and Treatment

, Volume 132, Issue 2, pp 429–437 | Cite as

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

  • Sharon Hensley Alford
  • Katherine Toy
  • Sofia D. Merajver
  • Celina G. Kleer
Preclinical Study

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.

Keywords

EZH2 Enhancer of zeste-2 Prognosis Recurrence Metastasis Breast cancer 

References

  1. 1.
    Sarrazin D, Dewar JA, Arriagada R et al (1986) Conservative management of breast cancer. Br J Surg 73:604–606PubMedCrossRefGoogle Scholar
  2. 2.
    Llombart-Cussac A (2008) Improving decision-making in early breast cancer: who to treat and how? Breast Cancer Res Treat 112(Suppl 1):15–24PubMedCrossRefGoogle Scholar
  3. 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 16:3219–3232PubMedCrossRefGoogle Scholar
  4. 4.
    Satijn DP, Otte AP (1999) Polycomb group protein complexes: do different complexes regulate distinct target genes? Biochim Biophys Acta 1447:1–16PubMedGoogle Scholar
  5. 5.
    Ringrose L, Paro R (2004) Epigenetic regulation of cellular memory by the Polycomb and Trithorax group proteins. Annu Rev Genet 38:413–443PubMedCrossRefGoogle Scholar
  6. 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 65:753–763PubMedCrossRefGoogle Scholar
  7. 7.
    Hess JL (2004) MLL: a histone methyltransferase disrupted in leukemia. Trends Mol Med 10:500–507PubMedCrossRefGoogle Scholar
  8. 8.
    Boyer LA, Plath K, Zeitlinger J et al (2006) Polycomb complexes repress developmental regulators in murine embryonic stem cells. Nature 441:349–353PubMedCrossRefGoogle Scholar
  9. 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 22:6070–6078PubMedCrossRefGoogle Scholar
  10. 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 28:843–853PubMedCrossRefGoogle Scholar
  11. 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 100:11606–11611PubMedCrossRefGoogle Scholar
  12. 12.
    Cao Q, Yu J, Dhanasekaran SM et al (2008) Repression of E-cadherin by the polycomb group protein EZH2 in cancer. Oncogene 27:7274–7284PubMedCrossRefGoogle Scholar
  13. 13.
    Zeidler M, Varambally S, Cao Q et al (2005) The Polycomb group protein EZH2 impairs DNA repair in breast epithelial cells. Neoplasia 7:1011–1019PubMedCrossRefGoogle Scholar
  14. 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 19:86–100PubMedCrossRefGoogle Scholar
  15. 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 71:2360–2370PubMedCrossRefGoogle Scholar
  16. 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 22:5323–5335PubMedCrossRefGoogle Scholar
  17. 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 24:268–273PubMedCrossRefGoogle Scholar
  18. 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 12:1168–1174PubMedCrossRefGoogle Scholar
  19. 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 5:481–488PubMedGoogle Scholar
  20. 20.
    Varambally S, Dhanasekaran SM, Zhou M et al (2002) The polycomb group protein EZH2 is involved in progression of prostate cancer. Nature 419:624–629PubMedCrossRefGoogle Scholar
  21. 21.
    Gown AM (2008) Current issues in ER and HER2 testing by IHC in breast cancer. Mod Pathol 21(Suppl 2):S8–S15PubMedCrossRefGoogle Scholar
  22. 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 100:229–235PubMedCrossRefGoogle Scholar
  23. 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 66:4095–4099PubMedCrossRefGoogle Scholar
  24. 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:R63CrossRefGoogle Scholar
  25. 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 16:2045–2051PubMedGoogle Scholar
  26. 26.
    Ding L, Kleer CG (2006) Enhancer of Zeste 2 as a marker of preneoplastic progression in the breast. Cancer Res 66:9352–9355PubMedCrossRefGoogle Scholar
  27. 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:R109CrossRefGoogle Scholar
  28. 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 75:252–257PubMedCrossRefGoogle Scholar
  29. 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 11:8570–8576PubMedCrossRefGoogle Scholar
  30. 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 16:349–353PubMedGoogle Scholar
  31. 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 97:484–491PubMedCrossRefGoogle Scholar
  32. 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 6:736–743PubMedCrossRefGoogle Scholar
  33. 33.
    Sudo T, Utsunomiya T, Mimori K et al (2005) Clinicopathological significance of EZH2 mRNA expression in patients with hepatocellular carcinoma. Br J Cancer 92:1754–1758PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC. 2011

Authors and Affiliations

  • Sharon Hensley Alford
    • 1
  • Katherine Toy
    • 2
    • 3
  • Sofia D. Merajver
    • 3
    • 4
  • Celina G. Kleer
    • 2
    • 3
  1. 1.Department of Public Health SciencesHenry Ford HospitalDetroitUSA
  2. 2.Department of PathologyUniversity of Michigan Medical School, 4217 Comprehensive Cancer CenterAnn ArborUSA
  3. 3.Comprehensive Cancer CenterUniversity of MichiganAnn ArborUSA
  4. 4.Department of Internal MedicineUniversity of MichiganAnn ArborUSA

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