Skip to main content
Log in

Expression Patterns of ER, HER2, and NM23-H1 in Breast Cancer Patients with Different Menopausal Status

Correlations with Metastasis

  • Original Research Article
  • Published:
Molecular Diagnosis & Therapy Aims and scope Submit manuscript

Abstract

Objective: This study was designed to analyze expression patterns of estrogen receptor (ER), human epidermal growth factor receptor-2 (HER2/ERBB2), and nonmetastatic protein 23 (NM23-H1/NME1) proteins in patients with invasive ductal carcinoma and different menopausal status to identify their relationships with axillary lymph node metastasis.

Materials and Methods: 213 pre-menopausal and 177 post-menopausal women diagnosed with invasive ductal carcinoma were evaluated for ER, HER2, and NM23-H1 protein expression by immunohistochemistry. When HER2 immunoreactivity was equivocal (category 2+), specimens were confirmed by fluorescence in situ hybridization.

Results: ER expression showed no correlation with menopausal status or lymph node metastasis (each p > 0.05). However, expression of ER was associated with negative expression of HER2 (r =−0.214, p < 0.05) and positive expression of NM23-H1 (r = 0.137, p < 0.05) in the pre-menopausal group. Over-expression of HER2 was correlated with menopausal status (r =−0.107, p < 0.05) and lymph node metastasis in the ER-negative post-menopausal group (r = 0.222, p < 0.05). NM23-H1 was associated with less lymph node metastasis in the ER-positive pre-menopausal group (r = −0.237, p < 0.05).

Conclusion: Our results indicated that expression patterns of ER, NM23-H1, and HER2 in primary breast cancer lesions warn that cells might have metastatic potential, which could assist clinicians to provide a more accurate prognosis and tailor therapeutic management for individual patients.

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

Access this article

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

Instant access to the full article PDF.

Fig. 1
Table I
Fig. 2
Table II
Table III
Fig. 3
Table IV
Fig. 4
Table V

Similar content being viewed by others

References

  1. Breasted JH. The Edwin Smith surgical papyrus. Chicago (IL): University of Chicago Press, 1990: 403–6

    Google Scholar 

  2. Ferlay J, Bray F, Pisani P, et al. GLOBOCAN 2002: cancer incidence, mortality and prevalence worldwide. IARC CancerBase No 5, version 2.0. Lyon: IARC Press, 2004

    Google Scholar 

  3. Jemal A, Siegel R, Ward E, et al. Cancer statistics, 2008. CA Cancer J Clin 2008; 58(2): 71–96

    Article  PubMed  Google Scholar 

  4. Parkin DM, Bray F, Ferlay J, et al. Global cancer statistics, 2002. CA Cancer J Clin 2005; 55(2): 74–108

    Article  PubMed  Google Scholar 

  5. Hu YH, Chisato N, Hiroyuki S, et al. Association of body mass index, physical activity, and reproductive histories with breast cancer: a case-control study in Gifu, Japan. Breast Cancer Res Treat 1997; 43: 65–72

    Article  PubMed  CAS  Google Scholar 

  6. Tung HT, Tsukuma H, Tanaka H, et al. Risk factors for breast cancer in Japan, with special attention to anthropometric measurements and reproductive history. Jpn J Clin Oncol 1999; 29: 137–46

    Article  PubMed  CAS  Google Scholar 

  7. Hilakivi-Clarke L, Cabanes A, Olivo S, et al. Do estrogens always increase breast cancer risk? J Steroid Biochem Mol Biol 2002; 80: 163–74

    Article  PubMed  CAS  Google Scholar 

  8. Lin KH, Wang WJ, Wu YH, et al. Activation of antimetastatic Nm23-H1 gene expression by estrogen and its alpha-receptor. Endocrinology 2002; 143(2): 467–75

    Article  PubMed  CAS  Google Scholar 

  9. Read LD, Keith Jr D, Slamon DJ, et al. Hormonal modulation of HER-2/neu protooncogene messenger ribonucleic acid and p185 protein expression in human breast cancer cell lines. Cancer Res 1990; 50(13): 3947–51

    PubMed  CAS  Google Scholar 

  10. Ménard S, Fortis S, Castiglioni F, et al. HER2 as a prognostic factor in breast cancer. Oncology 2001; 61Suppl. 2: 67–72

    PubMed  Google Scholar 

  11. Tovey S, Dunne B, Witton CJ, et al. Can molecular markers predict when to implement treatment with aromatase inhibitors in invasive breast cancer? Clin Cancer Res 2005; 11: 4835–42

    Article  PubMed  CAS  Google Scholar 

  12. Harari D, Yarden Y. Molecular mechanisms underlying ErbB2/HER2 action in breast cancer. Oncogene 2000; 19: 6102–14

    Article  PubMed  CAS  Google Scholar 

  13. Sugarbaker EV. Patterns of metastasis in human malignancies. Cancer Biol Rev 1981; 2: 235–78

    Google Scholar 

  14. Steeg PS, Bevilacqua G, Kopper L, et al. Evidence for a novel gene associated with low tumor metastatic potential. J Natl Cancer Inst 1988; 80(3): 200–4

    Article  PubMed  CAS  Google Scholar 

  15. Rosengard AM, Krutzsch HC, Shearn A, et al. Reduced Nm23/Awd protein in tumour metastasis and aberrant Drosophila development. Nature 1989; 342(6246): 177–80

    Article  PubMed  CAS  Google Scholar 

  16. Stahl JA, Leone A, Rosengard AM, et al. Identification of a second human nm23 gene, nm23-H2. Cancer Res 1991; 51(1): 445–9

    PubMed  CAS  Google Scholar 

  17. Venturelli D, Martinez R, Melotti P, et al. Overexpression of DR-nm23, a protein encoded by a member of the nm23 gene family, inhibits granulocyte differentiation and induces apoptosis in 32Dc13 myeloid cells. Proc Natl Acad Sci U S A 1995; 92(16): 7435–9

    Article  PubMed  CAS  Google Scholar 

  18. Milon L, Rousseau-Merck MF, Munier A, et al. nm23-H4, a new member of the family of human nm23/nucleoside diphosphate kinase genes localised on chromosome 16p13. Hum Genet 1997; 99(4): 550–7

    Article  PubMed  CAS  Google Scholar 

  19. Munier A, Feral C, Milon L, et al. A new human nm23 homologue (nm23-H5) specifically expressed in testis germinal cells. FEBS Lett 1998; 434(3): 289–94

    Article  PubMed  CAS  Google Scholar 

  20. Mehus JG, Deloukas P, Lambeth DO. NME6: a new member of the nm23/nucleoside diphosphate kinase gene family located on human chromosome 3p21.3. Hum Genet 1999; 104(6): 454–9

    Article  PubMed  CAS  Google Scholar 

  21. Tsuiki H, Nitta M, Furuya A, et al. A novel human nucleoside diphosphate (NDP) kinase, Nm23-H6, localizes in mitochondria and affects cytokinesis. J Cell Biochem 1999; 76(2): 254–69

    Article  PubMed  CAS  Google Scholar 

  22. Van Golen KL, Risin S, Staroselsky A, et al. Predominance of the metastatic phenotype in hybrids formed by fusion of mouse and human melanoma clones. Clin Exp Metastasis 1996; 14(2): 95–106

    Article  PubMed  Google Scholar 

  23. Padma P, Hozumi A, Ogawa K, et al. Molecular cloning and characterization of a thioredoxin/nucleoside diphosphate kinase related dynein intermediate chain from the ascidian, Ciona intestinalis. Gene 2001; 275(1): 177–83

    Article  PubMed  CAS  Google Scholar 

  24. Freije JM, MacDonald NJ, Steeg PS. Nm23 and tumour metastasis: basic and translational advances. Biochem Soc Symp 1998; 63: 261–71

    PubMed  CAS  Google Scholar 

  25. Orgéas CC, Hall P, Rosenberg LU, et al. The influence of menstrual risk factors on tumor characteristics and survival in postmenopausal breast cancer. Breast Cancer Res 2008; 10(6): R107

    Article  PubMed  Google Scholar 

  26. American Joint Committee on Cancer. AJCC cancer staging manual. 6th ed. New York: Springer-Verlag; 2003 [online]. Available from URL: http://www.cancerstaging.org/products/pasteditions.html [Accessed 2011 Jul 12]

    Google Scholar 

  27. Cheang MC, Chia SK, Voduc D, et al. Ki67 index, HER2 status, and prognosis of patients with luminal B breast cancer. J Natl Cancer Inst 2009; 101(10): 736–50

    Article  PubMed  CAS  Google Scholar 

  28. Guarneri V, Giovannelli S, Ficarra G, et al. Comparison of HER-2 and hormone receptor expression in primary breast cancers and asynchronous paired metastases: impact on patient management. Oncologist 2008; 13(8): 838–44

    Article  PubMed  CAS  Google Scholar 

  29. Rhee J, Han SW, Oh DY, et al. The clinicopathologic characteristics and prognostic significance of triple-negativity in node-negative breast cancer. BMC Cancer 2008; 8: 307

    Article  PubMed  Google Scholar 

  30. Wolff AC, Hammond ME, Schwartz JN, et al. American Society of Clinical Oncology/College of American Pathologists guideline recommendations for human epidermal growth factor receptor 2 testing in breast cancer. J Clin Oncol 2007; 25: 118–45

    Article  PubMed  CAS  Google Scholar 

  31. Belev B, Alerić I, Vrbanec D, et al. Nm23 gene product expression in invasive breast cancer: immunohistochemical analysis and clinicopathological correlation. Acta Oncol 2002; 41(4): 355–61

    Article  PubMed  CAS  Google Scholar 

  32. Gruber CJ, Tschugguel W, Schneeberger C, et al. Production and actions of estrogens. N Engl J Med 2002; 346(5): 340–52

    Article  PubMed  CAS  Google Scholar 

  33. Dickson RB, Huff KK, Spencer EM, et al. Induction of epidermal growth factor-related polypeptides by 17 beta-estradiol in MCF-7 human breast cancer cells. Endocrinology 1986; 118(1): 138–42

    Article  PubMed  CAS  Google Scholar 

  34. Wilding G, Lippman ME, Gelmann EP. Effects of steroid hormones and peptide growth factors on protooncogene c-fos expression in human breast cancer cells. Cancer Res 1988; 48(4): 802–5

    PubMed  CAS  Google Scholar 

  35. Dickson RB, McManaway ME, Lippman ME. Estrogen-induced factors of breast cancer cells partially replace estrogen to promote tumor growth. Science 1986; 232(4757): 1540–3

    Article  PubMed  CAS  Google Scholar 

  36. Dubik D, Dembinski TC, Shiu RP. Stimulation of c-myc oncogene expression associated with estrogen-induced proliferation of human breast cancer cells. Cancer Res 1987; 47 (24 Pt 1): 6517–21

    PubMed  CAS  Google Scholar 

  37. Sapino A, Pietribiasi F, Bussolati G, et al. Estrogen- and tamoxifen-induced rearrangement of cytoskeletal and adhesion structures in breast cancer MCF-7 cells. Cancer Res 1986; 46(5): 2526–31

    PubMed  CAS  Google Scholar 

  38. Huff KK, Lippman ME. Hormonal control of plasminogen activator secretion in ZR-75-1 human breast cancer cells in culture. Endocrinology 1984; 114(5): 1702–10

    Article  PubMed  CAS  Google Scholar 

  39. Albini A, Graf J, Kitten GT, et al. 17-β-Estradiol regulates and v-Ha-ras transfection constitutively enhances MCF7 breast cancer cell interactions with basement membrane. Proc Natl Acad Sci U S A 1986; 83(21): 8182–6

    Article  PubMed  CAS  Google Scholar 

  40. Capony F, Morisset M, Barrett AJ, et al. Phosphorylation, glycosylation and proteolytic activity of the 52-kD estrogen induced protein secreted by MCF-7 cells. J Cell Biol 1987; 104(2): 253–62

    Article  PubMed  CAS  Google Scholar 

  41. Laudadio J, Quigley DI, Tubbs R, et al. HER2 testing: a review of detection methodologies and their clinical performance. Expert Rev Mol Diagn 2007; 7(1): 53–64

    Article  PubMed  CAS  Google Scholar 

  42. Frogne T, Laenkholm AV, Lyng MB, et al. Determination of HER2 phosphorylation at tyrosine 1221/1222 improves prediction of poor survival for breast cancer patients with hormone receptor positive tumors. Breast Cancer Res 2009; 11(1): R11

    Article  PubMed  Google Scholar 

  43. Berno V, Amazit L, Hinojos C, et al. Activation of estrogen receptor-alpha by E2 or EGF induces temporally distinct patterns of large-scale chromatin modification and mRNA transcription. PLoS One 2008; 3(5): e2286

    Article  PubMed  Google Scholar 

  44. Baird DT, Horton R, Longcope C, et al. Steroid dynamics under steady-state conditions. Recent Prog Horm Res 1969; 25: 611–64

    PubMed  CAS  Google Scholar 

  45. Barrett-Lee PJ, Travers MT, McClelland RA, et al. Characterization of estrogen receptor messenger RNA in human breast cancer. Cancer Res 1987; 47: 6653–9

    PubMed  CAS  Google Scholar 

  46. Benz CC. Impact of aging on the biology of breast cancer. Crit Rev Oncol Hematol 2008; 66(1): 65–74

    Article  PubMed  Google Scholar 

  47. de la Rosa A, Williams RL, Steeg PS. Nm23/nucleoside diphosphate kinase: toward a structural and biochemical understanding of its biological functions. Bioessays 1995; 17(1): 53–62

    Article  PubMed  Google Scholar 

  48. Nakayama T, Ohtsuru A, Nakao K, et al. Expression in human hepatocellular carcinoma of nucleoside diphosphate kinase, a homologue of the nm23 gene product. J Natl Cancer Inst 1992; 84(17): 1349–54

    Article  PubMed  CAS  Google Scholar 

  49. Yamaguchi A, Urano T, Goi T, et al. Expression of human nm23-H1 and nm23-H2 proteins in hepatocellular carcinoma. Cancer 1994; 73(9): 2280–4

    Article  PubMed  CAS  Google Scholar 

  50. Iizuka N, Oka M, Noma T, et al. NM23-H1 and NM23-H2 messenger RNA abundance in human hepatocellular carcinoma. Cancer Res 1995; 55(3): 652–7

    PubMed  CAS  Google Scholar 

  51. Royds JA, Stephenson TJ, Rees RC, et al. Nm23 protein expression in ductal in situ and invasive human breast carcinoma. J Natl Cancer Inst 1993; 85(9): 727–31

    Article  PubMed  CAS  Google Scholar 

  52. Kodera Y, Isobe K, Yamauchi M, et al. Expression of nm23-H1 RNA levels in human gastric cancer tissues: a negative correlation with nodal metastasis. Cancer 1994; 73(2): 259–65

    Article  PubMed  CAS  Google Scholar 

  53. Mandai M, Konishi I, Koshiyama M, et al. Expression of metastasis-related nm23-H 1 and nm23-H2 genes in ovarian carcinomas: correlation with clinicopathology, EGFR, c-erbB-2, and c-erbB-3 genes, and sex steroid receptor expression. Cancer Res 1994; 54(7): 1825–30

    PubMed  CAS  Google Scholar 

  54. Viel A, Dall’Agnese L, Canzonieri V, et al. Suppressive role of the metastasis-related nm23-H1 gene in human ovarian carcinomas: association of high messenger RNA expression with lack of lymph node metastasis. Cancer Res 1995; 55(12): 2645–50

    PubMed  CAS  Google Scholar 

  55. Scambia G, Ferrandina G, Marone M, et al. nm23 in ovarian cancer: correlation with clinical outcome and other clinicopathologic and biochemical prognostic parameters. J Clin Oncol 1996; 14(2): 334–42

    PubMed  CAS  Google Scholar 

  56. Ozeki Y, Takishima K, Mamiya G. Immunohistochemical analysis of nm23/NDP kinase expression in human lung adenocarcinoma: association with tumor progression in Clara cell type. Jpn J Cancer Res 1994; 85(8): 840–6

    Article  PubMed  CAS  Google Scholar 

  57. Zafon C, Obiols G, Castellví J, et al. nm23-H1 immunoreactivity as a prognostic factor in differentiated thyroid carcinoma. J Clin Endocrinol Metab 2001; 86(8): 3975–80

    Article  PubMed  CAS  Google Scholar 

  58. Sirotkovic-Skerlev M, Krizanac S, Kapitanovic S, et al. Expression of c-myc, erbB-2, p53 and nm23-H1 gene product in benign and malignant breast lesions: coexpression and correlation with clinicopathologic parameters. Exp Mol Pathol 2005; 79(1): 42–50

    Article  PubMed  CAS  Google Scholar 

  59. Shiau AK, Barstad D, Loria PM, et al. The structural basis of estrogen receptor/coactivator recognition and the antagonism of this interaction by tamoxifen. Cell 1998; 95(7): 927–37

    Article  PubMed  CAS  Google Scholar 

  60. Driscoll MD, Sathya G, Muyan M, et al. Sequence requirements for estrogen receptor binding to estrogen response elements. J Biol Chem 1998; 273(45): 29321–30

    Article  PubMed  CAS  Google Scholar 

  61. Kato S, Tora L, Yamauchi J, et al. A far upstream estrogen response element of the ovalbumin gene contains several half-palindromic 5′-TGACC-3′ motifs acting synergistically. Cell 1992; 68(4): 731–42

    Article  PubMed  CAS  Google Scholar 

  62. Näär AM, Boutin JM, Lipkin SM, et al. The orientation and spacing of core DNA-binding motifs dictate selective transcriptional responses to three nuclear receptors. Cell 1991; 65(7): 1267–79

    Article  PubMed  Google Scholar 

  63. Curtis CD, Likhite VS, McLeod IX, et al. Interaction of the tumor metastasis suppressor nonmetastatic protein 23 homologue H1 and estrogen receptor A alters estrogen-responsive gene expression. Cancer Res 2007; 67(21): 10600–7

    Article  PubMed  CAS  Google Scholar 

  64. Ouatas T, Salerno M, Palmieri D, et al. Basic and translational advances in cancer metastasis: Nm23. J Bioenerg Biomembr 2003; 35: 73–9

    Article  PubMed  CAS  Google Scholar 

  65. Gershenwald JE, Thompson W, Mansfield PF, et al. Multi-institutional melanoma lymphatic mapping experience: the prognostic value of sentinel lymph node status in 612 stage I or II melanoma patients. J Clin Oncol 1999; 17: 976–83

    PubMed  CAS  Google Scholar 

  66. Beenken SW, Grizzle WE, Crowe DR, et al. Molecular biomarkers for breast cancer prognosis: coexpression of c-erbB-2 and p53. Ann Surg 2001; 233(5): 630–8

    Article  PubMed  CAS  Google Scholar 

  67. Tsutsui S, Ohno S, Murakami S, et al. Prognostic significance of the coexpression of p53 protein and c-erbB2 in breast cancer. Am J Surg 2003; 185: 165–7

    Article  PubMed  CAS  Google Scholar 

  68. Patani N, Mokbel K. Herceptin and breast cancer: an overview for surgeons. Surg Oncol 2010; 19(1): e11–21

    Article  PubMed  CAS  Google Scholar 

  69. Steeg PS, Horak CE, Miller KD. Clinical-translational approaches to the Nm23-H1 metastasis suppressor. Clin Cancer Res 2008; 14(16): 5006–12

    Article  PubMed  CAS  Google Scholar 

  70. Marshall JC, Lee JH, Steeg PS. Clinical-translational strategies for the elevation of Nm23-H1 metastasis suppressor gene expression. Mol Cell Biochem 2009; 329(1–2): 115–20

    Article  PubMed  CAS  Google Scholar 

  71. Steeg PS, Ouatas T, Halverson D, et al. Metastasis suppressor genes: basic biology and potential clinical use. Clin Breast Cancer 2003; 4: 51–62

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

Dong Su-Wei and Wang Lin contributed equally to this work.

The authors declare that they have no competing interests.

This study was supported by the National Natural Science Foundation of China (grant nos. 30671904, 30760014, and 81060185), the New Century Excellent Talent Supporting Project of the Ministry of Education of China (grant no. NCET-08-0923), the Cultivation Program for Reserve Talent of Middle-Young Aged Academic and Technology Leaders of Yunnan Province (grant no. 2006Y01-12), the Key Program of Science and Technology Project of Kunming (grant no. 07S060202), the Yunnan Provincial Applied Basic Research Program (grant nos. 2007C0022R, 2007C0025R, and 2007C0023R), the Science and Technology Program of Yunnan Province (grant no. 2007C009Z), the Yunnan Provincial Key Program for Applied Basic Research (grant no. 2008CC006), the Yunnan Provincial Project for Introduction and Cultivation of High-Level Talents (grant no. 20080C014), and the Creative Talent Team Program for High Incidence Lung Cancer Prevention and Cure, Yunnan, China (grant no. 20080c014).

The authors thank Rebekah L. Craig for providing English language and editorial assistance in the preparation of this manuscript.

Author information

Authors and Affiliations

Authors

Corresponding authors

Correspondence to Yong-Feng Jia or Xin Song.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Dong, SW., Wang, L., Sui, J. et al. Expression Patterns of ER, HER2, and NM23-H1 in Breast Cancer Patients with Different Menopausal Status. Mol Diag Ther 15, 211–219 (2011). https://doi.org/10.1007/BF03256412

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF03256412

Keywords

Navigation