Skip to main content
SpringerLink
Log in

Expression of estrogen receptor-α and Ki67 in relation to pathological and molecular features in early-onset infiltrating ductal carcinoma

  • Original Paper
  • Published:
Journal of Biomedical Science

Abstract

Estrogen causes breast cancer by triggering proliferation via an estrogen receptor (ER)-mediated mechanism. However, paradoxically, ERα, one of the two known ER subtypes, and the proliferation marker, Ki67, are not usually expressed in the same breast tumor. To explore whether ERα-positive tumors and proliferating (Ki67-positive) tumors have different tumorigenic characteristics, we performed an immunohistochemical study on 74 early-onset infiltrating ductal carcinomas of the breast. To test this hypothesis, we examined whether ERα-positive and Ki67-positive tumors showed differences in (i) pathological grade, (ii) three indices of tumor grade (tubule formation, nuclear pleomorphism, and mitotic number), and (iii) expression of important proteins implicated in breast tumorigenesis (cyclin D1, ErbB2, ATM, BRCA1, Rb, p53, and p21). The results of the multigenic analysis showed that ERα and Ki67 were the only two important markers significantly and independently associated with tumor grade, consistent with the above hypothesis. ERα-positive, Ki67-negative tumors frequently displayed a low tumor grade (i.e. being well differentiated), whereas Ki67-positive, ERα-negative tumors were more likely to exhibit a high tumor grade. In addition, positive ERα expression (46 of 74 cases, 62%) correlated well with positive cyclin D1 expression (p<0.005), less nuclear pleomorphism (p<0.001), and a low mitotic count (p < 0.005), whereas positive Ki67 expression (36 of 74 cases, 49%) correlated with reduced BRCA1 expression (p < 0.01) and high mitotic activity (p<0.01). These findings suggest that the expressions of ERα and Ki67 might be involved in distinct pathological and molecular features during breast cancer development.

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

Similar content being viewed by others

References

  1. Angèle S, Treilleux I, Tanière P, Martel-Planche G, Vuillaume M, Bailly C, Brémond A, Montesano R, Hall J. Abnormal expression of the ATM and TP53 genes in sporadic breast carcinomas. Clin Cancer Res 6:3536–3544;2000.

    PubMed  Google Scholar 

  2. Bartkova J, Lukas J, Muller H, Lutzhoft D, Strauss M, Bartek J. Cyclin D1 protein expression and function in human breast cancer. Int J Cancer 57:353–361;1994.

    PubMed  Google Scholar 

  3. Bates S, Parry D, Bonetta L, Vousden K, Dickson C, Peters G. Absence of cyclin D/cdk complexes in cells lacking functional retinoblastoma protein. Oncogene 9:1633–1640;1994.

    PubMed  Google Scholar 

  4. Breast Cancer Linkage Consortium. Pathology of familial breast cancer: differences between breast cancers in carriers of BRCA1 or BRCA2 mutations and sporadic cases. Lancet 349:1505–1510;1997.

    Google Scholar 

  5. Chappell SA, Johnson SM, Shaw JA, Walker RA. Expression of oestrogen receptor alpha variants in non-malignant breast and early invasive breast carcinomas. J Pathol 192:159–165;2000.

    Article  PubMed  Google Scholar 

  6. Clarke R, Howell A, Potten C, Anderson E. Dissociation between steroid receptor expression and cell proliferation in the human breast. Cancer Res 57:4987–4991;1997.

    PubMed  Google Scholar 

  7. Collecchi P, Passoni A, Rocchetta M, Gnesi E, Baldini E, Bevilacqua G. Cyclin-D1 expression in node-positive (N+) and node-negative (N−) infiltrating human mammary carcinomas. Int J Cancer 84:139–144;1999.

    Article  PubMed  Google Scholar 

  8. Dowdy SF, Hinds PW, Louie K, Reed SI, Arnold A, Weinberg RA. Physical interaction of the retinoblastoma protein with human D cyclins. Cell 73:499–511;1993.

    Article  PubMed  Google Scholar 

  9. Eppenberger-Castori S, Moore DH Jr, Thor AD, Edgerton SM, Kueng W, Eppenberger U, Benz CC. Age-associated biomarker profiles of human breast cancer. Int J Biochem Cell Biol 34:1318–1330;2002.

    Article  PubMed  Google Scholar 

  10. Fu YP, Yu JC, Cheng TC, Lou MA, Hsu GC, Wu CY, Chen ST, Wu HS, Wu PE, Shen CY. Breast cancer risk associated with genotypic polymorphism of the nonhomologous end-joining genes: a multigenic study on cancer susceptibility. Cancer Res 63:2440–2446;2003.

    PubMed  Google Scholar 

  11. Gerdes J, Lemke H, Baisch H, Wacker HH, Schwab U, Stein H. Cell cycle analysis of a cell proliferation-associated human nuclear antigen defined by the monoclonal antibody Ki-67. J Immunol 133:1710–1715;1984.

    PubMed  Google Scholar 

  12. Gillett C, Smith P, Gregory W, Richards M, Millis R, Peters G, Barnes D. Cyclin D1 and prognosis in human breast cancer. Int J Cancer 69:92–99;1996.

    Article  PubMed  Google Scholar 

  13. Han EK, Sgambato A, Jiang W, Zhang YJ, Santella RM, Doki Y, Cacace AM, Schieren I, Weinstein IB. Stable overexpression of cyclin D1 in a human mammary epithelial cell line prolongs the S-phase and inhibits growth. Oncogene 10:953–961;1995.

    PubMed  Google Scholar 

  14. Harvey J, Clark G, Osborne C, Allred D. Estrogen receptor status by immunohistochemistry is superior to the ligand binding assay for predicting response to adjuvant endocrine therapy in breast cancer. J Clin Oncol 17:1474–1481;1999.

    PubMed  Google Scholar 

  15. Hinds PW, Mittnacht S, Dulic V, Arnold A, Reed SI, Weinberg RA. Regulation of retinoblastoma protein functions by ectopic expression of human cyclins. Cell 70:993–1006;1992.

    Article  PubMed  Google Scholar 

  16. Horwitz K, Clarke C. Estrogens and progestins in mammary development and neoplasia. J Mammary Gland Biol Neoplasia 3:1–103;1998.

    Article  PubMed  Google Scholar 

  17. Jares P, Rey MJ, Fernandez PL, Campo E, Nadal A, Munoz M, Mallofre C, Muntane J, Nayach I, Estape J, Cardesa A. Cyclin D1 and retinoblastoma gene expression in human breast carcinoma: correlation with tumour proliferation and oestrogen receptor status. J Pathol 182:160–166;1997.

    Article  PubMed  Google Scholar 

  18. Jarvis EM, Kirk JA, Clarke CL. Loss of nuclear BRCA1 expression in breast cancers is associated with a highly proliferative tumor phenotype. Cancer Genet Cytogenet 101:109–115;1998.

    Article  PubMed  Google Scholar 

  19. Jensen EV, Cheng G, Palmieri C, Saji S, Mäkelä S, Noorden SV, Wahlström T, Warner M, Coombes RC, Gustafsson JÅ. Estrogen receptors and proliferation markers in primary and recurrent breast cancer. Proc Natl Acad Sci USA 98:15197–15202;2001.

    Article  PubMed  Google Scholar 

  20. Kato J, Matsushime H, Hiebert SW, Ewen ME, Sherr CJ. Direct binding of cyclin D to the retinoblastoma gene product (pRb) and pRb phosphorylation by the cyclin D-dependent kinase CDK4. Genes Dev 7:331–342;1993.

    PubMed  Google Scholar 

  21. Landberg G, Nielsen NH, Nilsson P, Emdin SO, Cajander J, Roos G. Telomerase activity is associated with cell cycle deregulation in human breast cancer. Cancer Res 57:549–554;1997.

    PubMed  Google Scholar 

  22. Le Doussal V, Tubiana-Hulin M, Friedman S, Hacene K, Spyratos F, Brunet M. Prognostic value of histologic grade nuclear components of Scarff-Bloom-Richardson (SBR). An improved score modification based on a multivariate analysis of 1262 invasive ductal breast carcinomas. Cancer 64:1914–1921;1989.

    PubMed  Google Scholar 

  23. Lukas J, Muller H, Bartkova J, Spitkovsky D, Kjerulff AA, Jansen-Durr P, Strauss M, Bartek J. DNA tumor virus oncoproteins and retinoblastoma gene mutations share the ability to relieve the cell's requirement for cyclin D1 function in G1. J Cell Biol 125:625–638;1994.

    Article  PubMed  Google Scholar 

  24. Lung JC, Chu JS, Yu JC, Yue CT, Lo YL, Shen CY, Wu CW. Aberrant expression of cell-cycle regulator cyclin D1 in breast cancer is related to chromosomal genomic instability. Genes Chromosomes Cancer 34:276–284;2002.

    Article  PubMed  Google Scholar 

  25. McMahon C, Suthiphongchai T, DiRenzo J, Ewen ME. P/CAF associates with cyclin D1 and potentiates its activation of the estrogen receptor. Proc Natl Acad Sci USA 96:5382–5387;1999.

    Article  PubMed  Google Scholar 

  26. Muller H, Lukas J, Schneider A, Warthoe P, Bartek J, Eilers M, Strauss M. Cyclin D1 expression is regulated by the retinoblastoma protein. Proc Natl Acad Sci USA 91:2945–2949;1994.

    PubMed  Google Scholar 

  27. Nilsson S, Makela S, Treuter E, Tujague M, Thomsen J, Andersson G, Enmark E, Pettersson K, Warner M, Gustafsson JA. Mechanisms of estrogen action. Physiol Rev 81:1535–1565;2001.

    PubMed  Google Scholar 

  28. Ricketts D. Estrogen and progesterone receptors in normal female breast. Cancer Res 51:1817–1822;1991.

    PubMed  Google Scholar 

  29. Ruffner H, Verma IM. BRCA1 is a cell cycle-regulated nuclear phosphoprotein. Proc Natl Acad Sci USA 94:7138–7143;1997.

    Article  PubMed  Google Scholar 

  30. Russo J, Ao X, Grill C, Russo IH. Pattern of distribution of cells positive for estrogen receptor α and progesterone receptor in relation to proliferating cells in the mammary gland. Breast Cancer Res Treat 53:217–227;1999.

    Article  PubMed  Google Scholar 

  31. Russo J, Hu YF, Yang X, Russo IH. Developmental, cellular, and molecular basis of human breast cancer. J Natl Cancer Inst Monogr 27:17–37;2000.

    PubMed  Google Scholar 

  32. Shaaban AM, Sloane JP, West CR, Foster CS. Breast cancer risk in usual ductal hyperplasia is defined by estrogen receptor-α and Ki-67 expression. Am J Pathol 160:597–604;2002.

    PubMed  Google Scholar 

  33. Shen CY, Yu JC, Lo YL, Kuo CH, Yue CT, Jou YS, Huang CS, Lung JC, Wu CW. Genomewide search for loss of heterozygosity using laser capture microdissected tissue of breast carcinoma: an implication for mutator phenotype and breast cancer pathogenesis. Cancer Res 60:3884–3892;2000.

    PubMed  Google Scholar 

  34. Shoker BS, Jarvis C, Clarke RB, Anderson E, Hewlett J, Davies MPA, Sibson DR, Sloane JP. Oestrogen receptor-positive proliferating cells in the normal and precancerous breast. Am J Pathol 155:1811–1815;1999.

    PubMed  Google Scholar 

  35. Sutherland RL, Prall OWJ, Alle KM, Wilcken NRC, Hui R, Ball JR, Sarcevic B, Henshall SM, Musgrove EA, Watts CKW. Cyclin-dependent kinases as downstream targets of oestrogen action: potential prognostic indicators and therapeutic targets. Endocri Rel Cancer 4:357–370;1997.

    Google Scholar 

  36. Tam SW, Theodoras AM, Shay JW, Draetta GF, Pagano M. Differential expression and regulation of cyclin D1 protein in normal and tumor cells: association with Cdk4 is required for cyclin D1 function in G1 progression. Oncogene 9:2663–2674;1994.

    PubMed  Google Scholar 

  37. van Diest PJ, Michalides RJAM, Jannink I, vander Valk P, Peterse HL, deJong JS, Meijer CJLM, Baak JPA. Cyclin D1 expression in invasive breast cancer. Correlations and prognostic value. Am J Pathol 150:705–711;1997.

    PubMed  Google Scholar 

  38. Yoshikawa K, Honda K, Inamoto T, Shinohara H, Yamauchi A, Suga K, Okuyama T, Shimada T, Kodama H, Noguchi S, Gazdar AF, Yamaoka Y, Takahashi R. Reduction of BRCA1 protein expression in Japanese sporadic breast carcinomas and its frequent loss in BRCA1-associated cases. Clin Cancer Res 5:1249–1261;1999.

    PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Graduate Institute of Life Sciences, National Defense Medical Center, China

    Shian-ling Ding

  2. Institute of Biomedical Sciences, Academia Sinica, 128 Academic Road, 11529, Nankang, Taipei, Taiwan (ROC)

    Shian-ling Ding & Chen-Yang Shen

  3. Department of Nursing, Kang-Ning Junior College of Medical Care and Management, China

    Shian-ling Ding

  4. Department of Pathology, Tri-Service General Hospital, National Defense Medical Center, China

    Lai-Fa Sheu

  5. Department of Surgery, Tri-Service General Hospital, National Defense Medical Center, China

    Jyh-Cherng Yu

  6. Department of Surgery, Cardinal Tien Hospital and Fu-Jen Catholic University, Taipei, Taiwan, ROC

    Tseng-Long Yang

  7. Department of Pathology, Mackay Memorial Hospital, Cardinal Tien Hospital and Fu-Jen Catholic University, Taipei, Taiwan, ROC

    BeFong Chen

  8. Department of Section of Pathology, Cardinal Tien Hospital and Fu-Jen Catholic University, Taipei, Taiwan, ROC

    Fur-jiang Leu

Authors
  1. Shian-ling Ding
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Lai-Fa Sheu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jyh-Cherng Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Tseng-Long Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. BeFong Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Fur-jiang Leu
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Chen-Yang Shen
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ding, Sl., Sheu, LF., Yu, JC. et al. Expression of estrogen receptor-α and Ki67 in relation to pathological and molecular features in early-onset infiltrating ductal carcinoma. J Biomed Sci 11, 911–919 (2004). https://doi.org/10.1007/BF02254376

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF02254376

Key Words

Search

Navigation