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Invasive breast carcinomas in Ghana: high frequency of high grade, basal-like histology and high EZH2 expression

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Abstract

Breast cancer in African-American women has a worse outcome than in Caucasian women. The ancestors of most African-American women come from West Africa, including Ghana. The Polycomb group protein EZH2 is a marker of poor outcome in breast cancers from Caucasian women. The histopathological features and biomarker expression of African breast cancers remain obscure. Here, we investigated a cohort of Ghanaian breast cancers to better define the prevalent tumor types and to test if EZH2 protein may identify aggressive tumors. A group of 169 breast tissues (100 invasive carcinomas and 69 benign) from women treated at Komfo Anoyke Teaching Hospital between 2006 and 2011 were histologically classified and investigated for EZH2 expression. EZH2 nuclear expression we defined as high or low following previously published criteria. Of the 100 invasive carcinomas, 89 % were ductal, 2 % were lobular, and 9 % were metaplastic. Basal-like pathological features were present in 30 % of the tumors. Of the invasive carcinomas, 7 % were grade 1, 41 % grade 2, and 52 % grade 3. EZH2 protein was overexpressed in invasive carcinomas compared to benign breast (p < 0.0001). In invasive carcinomas nuclear EZH2 overexpression was significantly associated with basal-like subtype (p = 0.03) and high histologic grade (p < 0.05). Cytoplasmic EZH2, which has not been previously reported, was present in 16 % of invasive carcinomas and it was associated with triple negative status (p = 0.02). Our results provide the first comprehensive histopathological study of this patient population and uncover the association of EZH2 with high grade and basal-like tumors. We provide the basis for further detailed investigations on this cohort to advance diagnosis and treatment of African and African-American women.

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References

  1. Smigal C et al (2006) Trends in breast cancer by race and ethnicity: update 2006. CA Cancer J Clin 56(3):168–183

    Article  PubMed  Google Scholar 

  2. Eley JW et al (1994) Racial differences in survival from breast cancer. Results of the National Cancer Institute Black/White Cancer Survival Study. JAMA 272(12):947–954

    Article  PubMed  CAS  Google Scholar 

  3. Smith-Bindman R et al (2006) Does utilization of screening mammography explain racial and ethnic differences in breast cancer? Ann Intern Med 144(8):541–553

    PubMed  Google Scholar 

  4. Diaz LK et al (2007) Triple negative breast carcinoma and the basal phenotype: from expression profiling to clinical practice. Adv Anat Pathol 14(6):419–430

    Article  PubMed  CAS  Google Scholar 

  5. Carey LA et al (2006) Race, breast cancer subtypes, and survival in the carolina breast cancer study. JAMA 295(21):2492–2502

    Article  PubMed  CAS  Google Scholar 

  6. Kim MJ et al (2006) Clinicopathologic significance of the basal-like subtype of breast cancer: a comparison with hormone receptor and Her2/neu-overexpressing phenotypes. Hum Pathol 37(9):1217–1226

    Article  PubMed  CAS  Google Scholar 

  7. Rakha EA, Reis-Filho JS, Ellis IO (2008) Basal-like breast cancer: a critical review. J Clin Oncol 26(15):2568–2581

    Article  PubMed  Google Scholar 

  8. Yang XR et al (2007) Differences in risk factors for breast cancer molecular subtypes in a population-based study. Cancer Epidemiol Biomarkers Prev 16(3):439–443

    Article  PubMed  CAS  Google Scholar 

  9. Livasy CA et al (2006) Phenotypic evaluation of the basal-like subtype of invasive breast carcinoma. Mod Pathol 19(2):264–271

    Article  PubMed  CAS  Google Scholar 

  10. Fulford LG et al (2006) Specific morphological features predictive for the basal phenotype in grade 3 invasive ductal carcinoma of breast. Histopathology 49(1):22–34

    Article  PubMed  CAS  Google Scholar 

  11. Ding L et al (2006) Identification of EZH2 as a molecular marker for a precancerous state in morphologically normal breast tissues. Cancer Res 66(8):4095–4099

    Article  PubMed  CAS  Google Scholar 

  12. Kleer CG 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(20):11606–11611

    Article  PubMed  CAS  Google Scholar 

  13. Alford SH et al (2012) Increased risk for distant metastasis in patients with familial early-stage breast cancer and high EZH2 expression. Breast Cancer Res Treat 132(2):429–437

    Article  PubMed  CAS  Google Scholar 

  14. Pietersen AM et al (2008) EZH2 and BMI1 inversely correlate with prognosis and TP53 mutation in breast cancer. Breast Cancer Res 10(6):R109

    Article  PubMed  Google Scholar 

  15. Bachmann IM 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(2):268–273

    Article  PubMed  CAS  Google Scholar 

  16. Raaphorst FM et al (2003) Poorly differentiated breast carcinoma is associated with increased expression of the human polycomb group EZH2 gene. Neoplasia 5(6):481–488

    PubMed  CAS  Google Scholar 

  17. Gonzalez ME et al (2009) Downregulation of EZH2 decreases growth of estrogen receptor-negative invasive breast carcinoma and requires BRCA1. Oncogene 28(6):843–853

    Article  PubMed  Google Scholar 

  18. Chase A, Cross NC (2011) Aberrations of EZH2 in cancer. Clin Cancer Res 17(9):2613–2618

    Article  PubMed  CAS  Google Scholar 

  19. Stark A, Kleer CG, Martin I, Baffour A, Nsiah-Asare A, Takyi V, Braman M, Zarbo R, Wicha MS, Newman LA (2010) African ancestry and higher prevalence of triple negative breast cancer: findings from an international study. Cancer 116(21):4926–4932

    Article  PubMed  Google Scholar 

  20. Huo D et al (2009) Population differences in breast cancer: survey in indigenous African women reveals over-representation of triple-negative breast cancer. J Clin Oncol 27(27):4515–4521

    Article  PubMed  CAS  Google Scholar 

  21. 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(6):2360–2370

    Article  PubMed  CAS  Google Scholar 

  22. Kunju LP et al (2011) EZH2 and ALDH-1 mark breast epithelium at risk for breast cancer development. Mod Pathol 24(6):786–793

    Article  PubMed  CAS  Google Scholar 

  23. Newman LA et al (2006) Meta-analysis of survival in African American and white American patients with breast cancer: ethnicity compared with socioeconomic status. J Clin Oncol 24(9):1342–1349

    Article  PubMed  Google Scholar 

  24. Chlebowski RT et al (2005) Ethnicity and breast cancer: factors influencing differences in incidence and outcome. J Natl Cancer Inst 97(6):439–448

    Article  PubMed  Google Scholar 

  25. Nalwoga H et al (2007) Frequency of the basal-like phenotype in African breast cancer. APMIS 115(12):1391–1399

    Article  PubMed  Google Scholar 

  26. Ijaduola TG, Smith EB (1998) Pattern of breast cancer among white-American, African-American, and nonimmigrant west-African women. J Natl Med Assoc 90(9):547–551

    PubMed  CAS  Google Scholar 

  27. Awadelkarim KD et al (2011) Basal-like phenotype in a breast carcinoma case series from Sudan: prevalence and clinical/pathological correlations. Patholog Res Int 2011:806831

    PubMed  Google Scholar 

  28. Rosen PP (2008) Rosen’s breast pathology, in Rosen’s breast pathology. In: Rosen PP (ed) Lippincott Williams & Wilkins, Philadelphia

  29. Collett K 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(4):1168–1174

    Article  PubMed  CAS  Google Scholar 

  30. Bracken AP et al (2003) EZH2 is downstream of the pRB-E2F pathway, essential for proliferation and amplified in cancer. EMBO J 22(20):5323–5335

    Article  PubMed  CAS  Google Scholar 

  31. Gong Y et al (2011) Polycomb group protein EZH2 is frequently expressed in inflammatory breast cancer and is predictive of worse clinical outcome. Cancer 117(24):5476–5484

    Article  PubMed  CAS  Google Scholar 

  32. Ding L, Kleer CG (2006) Enhancer of Zeste 2 as a marker of preneoplastic progression in the breast. Cancer Res 66(19):9352–9355

    Article  PubMed  CAS  Google Scholar 

  33. Chen H, Rossier C, Antonarakis SE (1996) Cloning of a human homolog of the Drosophila enhancer of zeste gene (EZH2) that maps to chromosome 21q22.2. Genomics 38(1):30–37

    Article  PubMed  CAS  Google Scholar 

  34. Laible G 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(11):3219–3232

    Article  PubMed  CAS  Google Scholar 

  35. Sewalt RG et al (1998) Characterization of interactions between the mammalian polycomb-group proteins Enx1/EZH2 and EED suggests the existence of different mammalian polycomb-group protein complexes. Mol Cell Biol 18(6):3586–3595

    PubMed  CAS  Google Scholar 

  36. Laible G et al (1999) The murine polycomb-group genes Ezh1 and Ezh2 map close to Hox gene clusters on mouse chromosomes 11 and 6. Mamm Genome 10(3):311–314

    Article  PubMed  CAS  Google Scholar 

  37. Varambally S et al (2002) The polycomb group protein EZH2 is involved in progression of prostate cancer. Nature 419(6907):624–629

    Article  PubMed  CAS  Google Scholar 

  38. Kuzmichev A et al (2004) Different EZH2-containing complexes target methylation of histone H1 or nucleosomal histone H3. Mol Cell 14(2):183–193

    Article  PubMed  CAS  Google Scholar 

  39. Su IH et al (2005) Polycomb group protein ezh2 controls actin polymerization and cell signaling. Cell 121(3):425–436

    Article  PubMed  CAS  Google Scholar 

  40. van der Vlag J, Otte AP (1999) Transcriptional repression mediated by the human polycomb-group protein EED involves histone deacetylation. Nat Genet 23(4):474–478

    Article  PubMed  Google Scholar 

  41. Huang L, Pardee AB (2000) Suberoylanilide hydroxamic acid as a potential therapeutic agent for human breast cancer treatment. Mol Med 6(10):849–866

    PubMed  CAS  Google Scholar 

  42. Miranda TB et al (2009) DZNep is a global histone methylation inhibitor that reactivates developmental genes not silenced by DNA methylation. Mol Cancer Ther 8(6):1579–1588

    Article  PubMed  CAS  Google Scholar 

  43. Tan J et al (2007) Pharmacologic disruption of Polycomb-repressive complex 2-mediated gene repression selectively induces apoptosis in cancer cells. Genes Dev 21(9):1050–1063

    Article  PubMed  CAS  Google Scholar 

  44. Puppe J 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 Res 11(4):R63

    Article  PubMed  Google Scholar 

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Acknowledgements

This work was supported by NIH grants R01 CA107469, R01 CA125577 and U01CA154224 (to CGK), and the National Institutes of Health through the University of Michigan’s Cancer Center Support Grant (5 P30 CA46592). This work was also sponsored by the Susan G. Komen for the Cure (to LAN).

Conflict of interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

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

    Judy Pang, Kathy A. Toy & Celina G. Kleer

  2. Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, MI, USA

    Ken A. Griffith, Lisa A. Newman & Celina G. Kleer

  3. Department of Biostatistics, University of Michigan Medical School, Ann Arbor, MI, USA

    Ken A. Griffith

  4. Department of Surgery, University of Michigan Medical School, Ann Arbor, MI, USA

    Lisa A. Newman

  5. Department of Radiation Oncology, Komfo Anoyke Teaching Hospital (KATH), Kumasi, Ghana

    Baffour Awuah

  6. Department of Pathology, Komfo Anoyke Teaching Hospital (KATH), Kumasi, Ghana

    Solomon Quayson

Authors
  1. Judy Pang
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  2. Kathy A. Toy
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  3. Ken A. Griffith
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  4. Baffour Awuah
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  5. Solomon Quayson
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  6. Lisa A. Newman
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  7. Celina G. Kleer
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Corresponding author

Correspondence to Celina G. Kleer.

Additional information

Drs. Celina G. Kleer and Lisa A. Newman are co-senior authors.

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Pang, J., Toy, K.A., Griffith, K.A. et al. Invasive breast carcinomas in Ghana: high frequency of high grade, basal-like histology and high EZH2 expression. Breast Cancer Res Treat 135, 59–66 (2012). https://doi.org/10.1007/s10549-012-2055-z

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  • DOI: https://doi.org/10.1007/s10549-012-2055-z

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