Skip to main content

Mammary field cancerization: molecular evidence and clinical importance

Breast Cancer Research and Treatment volume 118, pages 229–239 (2009)Cite this article

Abstract

The term “field cancerization” originally denoted the presence of histologically abnormal tissue/cells surrounding primary tumors of the head and neck. Similar concepts with different and continuously changing definitions have been used for other types of tumors including breast adenocarcinoma, where field cancerization presently denotes the occurrence of molecular alterations in histologically normal tissues surrounding areas of overt cancer. Human mammary tissue morphology lends itself to the proposed concepts of field cancerization, which may include the gradual accumulation of genetic and other aberrations in stationary epithelial cells with intact morphology, or the spread of histologically normal yet genetically aberrant epithelial cells within mammary tissue. In this report, we review published molecular genetic, epigenetic, and gene expressional data in support of field cancerization in human mammary tissues. We then discuss the clinical implications of mammary field cancerization, including its source for potential biomarkers with diagnostic/prognostic potential, and its relationship to surgical margins and disease recurrence. We conclude with a future outlook on further research on mammary field cancerization addressing experimental methods, as well as the development of possible models and integrated approaches to gain a better understanding of the underlying mechanisms with the ultimate goal of developing clinical applications.

This is a preview of subscription content, access via your institution.

Access options

Buy single article

Instant access to the full article PDF.

43,34 €

Price includes VAT (Finland)
Tax calculation will be finalised during checkout.

Fig. 1

References

  1. Slaughter DP, Southwick HW, Smejkal W (1953) Field cancerization in oral stratified squamous epithelium; clinical implications of multicentric origin. Cancer 6:963–968

    Article  CAS  PubMed  Google Scholar 

  2. Dakubo GD, Jakupciak JP, Birch-Machin MA, Parr RL (2007) Clinical implications and utility of field cancerization. Cancer Cell Int 7:2

    Article  PubMed  Google Scholar 

  3. Braakhuis BJ, Tabor MP, Kummer JA, Leemans CR, Brakenhoff RH (2003) A genetic explanation of Slaughter’s concept of field cancerization: evidence and clinical implications. Cancer Res 63:1727–1730

    CAS  PubMed  Google Scholar 

  4. Hockel M, Dornhofer N (2005) The hydra phenomenon of cancer: why tumors recur locally after microscopically complete resection. Cancer Res 65:2997–3002

    PubMed  Google Scholar 

  5. Lim W, Park EH, Choi SL, Seo JY, Kim HJ, Chang MA, Ku BK, Son B, Ahn SH (2009) Breast conserving surgery for multifocal breast cancer. Ann Surg 249:87–90

    Article  PubMed  Google Scholar 

  6. Chen Y, Thompson W, Semenciw R, Mao Y (1999) Epidemiology of contralateral breast cancer. Cancer Epidemiol Biomark Prev 8:855–861

    CAS  Google Scholar 

  7. Jain S, Rezo A, Shadbolt B, Dahlstrom JE (2009) Synchronous multiple ipsilateral breast cancers: implications for patient management. Pathology 41:57–67

    Article  PubMed  Google Scholar 

  8. Coyle YM (2004) The effect of environment on breast cancer risk. Breast Cancer Res Treat 84:273–288

    Article  CAS  PubMed  Google Scholar 

  9. Huston TL, Simmons RM (2005) Locally recurrent breast cancer after conservation therapy. Am J Surg 189:229–235

    Article  PubMed  Google Scholar 

  10. Radisky ES, Radisky DC (2007) Stromal induction of breast cancer: inflammation and invasion. Rev Endocr Metab Disord 8:279–287

    Article  PubMed  Google Scholar 

  11. Fukino K, Shen L, Matsumoto S, Morrison CD, Mutter GL, Eng C (2004) Combined total genome loss of heterozygosity scan of breast cancer stroma and epithelium reveals multiplicity of stromal targets. Cancer Res 64:7231–7236

    Article  CAS  PubMed  Google Scholar 

  12. Moinfar F, Man YG, Arnould L, Bratthauer GL, Ratschek M, Tavassoli FA (2000) Concurrent and independent genetic alterations in the stromal and epithelial cells of mammary carcinoma: implications for tumorigenesis. Cancer Res 60:2562–2566

    CAS  PubMed  Google Scholar 

  13. Kurose K, Hoshaw-Woodard S, Adeyinka A, Lemeshow S, Watson PH, Eng C (2001) Genetic model of multi-step breast carcinogenesis involving the epithelium and stroma: clues to tumour-microenvironment interactions. Hum Mol Genet 10:1907–1913

    Article  CAS  PubMed  Google Scholar 

  14. Fukino K, Shen L, Patocs A, Mutter GL, Eng C (2007) Genomic instability within tumor stroma and clinicopathological characteristics of sporadic primary invasive breast carcinoma. Jama 297:2103–2111

    Article  CAS  PubMed  Google Scholar 

  15. O’Connell P, Pekkel V, Fuqua SA, Osborne CK, Clark GM, Allred DC (1998) Analysis of loss of heterozygosity in 399 premalignant breast lesions at 15 genetic loci. J Natl Cancer Inst 90:697–703

    Article  PubMed  Google Scholar 

  16. Larson PS, de las Morenas A, Cerda SR, Bennett SR, Cupples LA, Rosenberg CL (2006) Quantitative analysis of allele imbalance supports atypical ductal hyperplasia lesions as direct breast cancer precursors. J Pathol 209:307–316

    Article  CAS  PubMed  Google Scholar 

  17. Heaphy CM, Bisoffi M, Joste NE, Baumgartner KB, Baumgartner RN, Griffith JK (2008) Genomic instability demonstrates similarity between DCIS and invasive carcinomas. Breast Cancer Res Treat. doi:10.1007/s10549-008-0165-4

  18. Larson PS, de las Morenas A, Cupples LA, Huang K, Rosenberg CL (1998) Genetically abnormal clones in histologically normal breast tissue. Am J Pathol 152:1591–1598

    CAS  PubMed  Google Scholar 

  19. Larson PS, de las Morenas A, Bennett SR, Cupples LA, Rosenberg CL (2002) Loss of heterozygosity or allele imbalance in histologically normal breast epithelium is distinct from loss of heterozygosity or allele imbalance in co-existing carcinomas. Am J Pathol 161:283–290

    PubMed  Google Scholar 

  20. Larson PS, Schlechter BL, de las Morenas A, Garber JE, Cupples LA, Rosenberg CL (2005) Allele imbalance, or loss of heterozygosity, in normal breast epithelium of sporadic breast cancer cases and BRCA1 gene mutation carriers is increased compared with reduction mammoplasty tissues. J Clin Oncol 23:8613–8619

    Article  CAS  PubMed  Google Scholar 

  21. Heaphy CM, Bisoffi M, Fordyce CA, Haaland CM, Hines WC, Joste NE, Griffith JK (2006) Telomere DNA content and allelic imbalance demonstrate field cancerization in histologically normal tissue adjacent to breast tumors. Int J Cancer 119:108–116

    Article  CAS  PubMed  Google Scholar 

  22. Forsti A, Louhelainen J, Soderberg M, Wijkstrom H, Hemminki K (2001) Loss of heterozygosity in tumour-adjacent normal tissue of breast and bladder cancer. Eur J Cancer 37:1372–1380

    Article  CAS  PubMed  Google Scholar 

  23. Ellsworth DL, Ellsworth RE, Liebman MN, Hooke JA, Shriver CD (2004) Genomic instability in histologically normal breast tissues: implications for carcinogenesis. Lancet Oncol 5:753–758

    Article  CAS  PubMed  Google Scholar 

  24. Ellsworth DL, Ellsworth RE, Love B, Deyarmin B, Lubert SM, Mittal V, Shriver CD (2004) Genomic patterns of allelic imbalance in disease free tissue adjacent to primary breast carcinomas. Breast Cancer Res Treat 88:131–139

    Article  CAS  PubMed  Google Scholar 

  25. Ellsworth RE, Ellsworth DL, Lubert SM, Hooke J, Somiari RI, Shriver CD (2003) High-throughput loss of heterozygosity mapping in 26 commonly deleted regions in breast cancer. Cancer Epidemiol Biomark Prev 12:915–919

    CAS  Google Scholar 

  26. Ellsworth DL, Ellsworth RE, Love B, Deyarmin B, Lubert SM, Mittal V, Hooke JA, Shriver CD (2004) Outer breast quadrants demonstrate increased levels of genomic instability. Ann Surg Oncol 11:861–868

    Article  PubMed  Google Scholar 

  27. Botti C, Pescatore B, Mottolese M, Sciarretta F, Greco C, Di Filippo F, Gandolfo GM, Cavaliere F, Bovani R, Varanese A, Cianciulli AM (2000) Incidence of chromosomes 1 and 17 aneusomy in breast cancer and adjacent tissue: an interphase cytogenetic study. J Am Coll Surg 190:530–539

    Article  CAS  PubMed  Google Scholar 

  28. Desmaze C, Soria JC, Freulet-Marriere MA, Mathieu N, Sabatier L (2003) Telomere-driven genomic instability in cancer cells. Cancer Lett 194:173–182

    Article  CAS  PubMed  Google Scholar 

  29. Bohr VA, Anson RM (1995) DNA damage, mutation and fine structure DNA repair in aging. Mutat Res 338:25–34

    CAS  PubMed  Google Scholar 

  30. Olovnikov AM (1971) Principle of marginotomy in template synthesis of polynucleotides. Doklady Akademii nauk SSSR 201:1496–1499

    CAS  PubMed  Google Scholar 

  31. Smogorzewska A, van Steensel B, Bianchi A, Oelmann S, Schaefer MR, Schnapp G, de Lange T (2000) Control of human telomere length by TRF1 and TRF2. Mol Cell Biol 20:1659–1668

    Article  CAS  PubMed  Google Scholar 

  32. Meeker AK, Hicks JL, Gabrielson E, Strauss WM, De Marzo AM, Argani P (2004) Telomere shortening occurs in subsets of normal breast epithelium as well as in situ and invasive carcinoma. Am J Pathol 164:925–935

    PubMed  Google Scholar 

  33. Meeker AK, Argani P (2004) Telomere shortening occurs early during breast tumorigenesis: a cause of chromosome destabilization underlying malignant transformation? J Mammary Gland Biol Neoplasia 9:285–296

    Article  PubMed  Google Scholar 

  34. Kurabayashi R, Takubo K, Aida J, Honma N, Poon SS, Kammori M, Izumiyama-Shimomura N, Nakamura KI, Tsuji EI, Matsuura M, Ogawa T, Kaminishi M (2008) Luminal and cancer cells in the breast show more rapid telomere shortening than myoepithelial cells and fibroblasts. Human Pathol 39:1647–1655

    Article  CAS  Google Scholar 

  35. Bloushtain-Qimron N, Yao J, Snyder EL, Shipitsin M, Campbell LL, Mani SA, Hu M, Chen H, Ustyansky V, Antosiewicz JE, Argani P, Halushka MK, Thomson JA, Pharoah P, Porgador A, Sukumar S, Parsons R, Richardson AL, Stampfer MR, Gelman RS, Nikolskaya T, Nikolsky Y, Polyak K (2008) Cell type-specific DNA methylation patterns in the human breast. Proc Natl Acad Sci USA 105:14076–14081

    Article  CAS  PubMed  Google Scholar 

  36. Friso S, Choi SW (2002) Gene-nutrient interactions and DNA methylation. J Nutr 132:2382S–2387S

    CAS  PubMed  Google Scholar 

  37. Seitz HK, Stickel F (2007) Molecular mechanisms of alcohol-mediated carcinogenesis. Nat Rev 7:599–612

    CAS  Article  Google Scholar 

  38. Li S, Hursting SD, Davis BJ, McLachlan JA, Barrett JC (2003) Environmental exposure, DNA methylation, and gene regulation: lessons from diethylstilbesterol-induced cancers. Ann N Y Acad Sci 983:161–169

    Article  CAS  PubMed  Google Scholar 

  39. Bradley C, van der Meer R, Roodi N, Yan H, Chandrasekharan MB, Sun ZW, Mernaugh RL, Parl FF (2007) Carcinogen-induced histone alteration in normal human mammary epithelial cells. Carcinogenesis 28:2184–2192

    Article  CAS  PubMed  Google Scholar 

  40. Kanai Y (2008) Alterations of DNA methylation and clinicopathological diversity of human cancers. Pathol Int 58:544–558

    Article  CAS  PubMed  Google Scholar 

  41. Dworkin AM, Huang TH, Toland AE (2009) Epigenetic alterations in the breast: implications for breast cancer detection, prognosis and treatment. Semin Cancer Biol 19:165–171

    Article  CAS  PubMed  Google Scholar 

  42. Yan PS, Venkataramu C, Ibrahim A, Liu JC, Shen RZ, Diaz NM, Centeno B, Weber F, Leu YW, Shapiro CL, Eng C, Yeatman TJ, Huang TH (2006) Mapping geographic zones of cancer risk with epigenetic biomarkers in normal breast tissue. Clin Cancer Res 12:6626–6636

    Article  CAS  PubMed  Google Scholar 

  43. Cheng AS, Culhane AC, Chan MW, Venkataramu CR, Ehrich M, Nasir A, Rodriguez BA, Liu J, Yan PS, Quackenbush J, Nephew KP, Yeatman TJ, Huang TH (2008) Epithelial progeny of estrogen-exposed breast progenitor cells display a cancer-like methylome. Cancer Res 68:1786–1796

    Article  CAS  PubMed  Google Scholar 

  44. Umbricht CB, Evron E, Gabrielson E, Ferguson A, Marks J, Sukumar S (2001) Hypermethylation of 14–3-3 sigma (stratifin) is an early event in breast cancer. Oncogene 20:3348–3353

    Article  CAS  PubMed  Google Scholar 

  45. Tlsty TD, Crawford YG, Holst CR, Fordyce CA, Zhang J, McDermott K, Kozakiewicz K, Gauthier ML (2004) Genetic and epigenetic changes in mammary epithelial cells may mimic early events in carcinogenesis. J Mammary Gland Biol Neoplasia 9:263–274

    Article  PubMed  Google Scholar 

  46. Holst CR, Nuovo GJ, Esteller M, Chew K, Baylin SB, Herman JG, Tlsty TD (2003) Methylation of p16(INK4a) promoters occurs in vivo in histologically normal human mammary epithelia. Cancer Res 63:1596–1601

    CAS  PubMed  Google Scholar 

  47. Lewis CM, Cler LR, Bu DW, Zochbauer-Muller S, Milchgrub S, Naftalis EZ, Leitch AM, Minna JD, Euhus DM (2005) Promoter hypermethylation in benign breast epithelium in relation to predicted breast cancer risk. Clin Cancer Res 11:166–172

    CAS  PubMed  Google Scholar 

  48. Braakhuis BJ, Leemans CR, Brakenhoff RH (2004) Using tissue adjacent to carcinoma as a normal control: an obvious but questionable practice. J Pathol 203:620–621

    Article  PubMed  Google Scholar 

  49. Finak G, Sadekova S, Pepin F, Hallett M, Meterissian S, Halwani F, Khetani K, Souleimanova M, Zabolotny B, Omeroglu A, Park M (2006) Gene expression signatures of morphologically normal breast tissue identify basal-like tumors. Breast Cancer Res 8:R58

    Article  PubMed  CAS  Google Scholar 

  50. Tripathi A, King C, de la Morenas A, Perry VK, Burke B, Antoine GA, Hirsch EF, Kavanah M, Mendez J, Stone M, Gerry NP, Lenburg ME, Rosenberg CL (2008) Gene expression abnormalities in histologically normal breast epithelium of breast cancer patients. Int J Cancer 122:1557–1566

    Article  CAS  PubMed  Google Scholar 

  51. Baird DM (2008) Mechanisms of telomeric instability. Cytogenet Genome Res 122:308–314

    Article  CAS  PubMed  Google Scholar 

  52. Elenbaas B, Spirio L, Koerner F, Fleming MD, Zimonjic DB, Donaher JL, Popescu NC, Hahn WC, Weinberg RA (2001) Human breast cancer cells generated by oncogenic transformation of primary mammary epithelial cells. Genes Dev 15:50–65

    Article  CAS  PubMed  Google Scholar 

  53. Hines WC, Fajardo AM, Joste NE, Bisoffi M, Griffith JK (2005) Quantitative and spatial measurements of telomerase reverse transcriptase expression within normal and malignant human breast tissues. Mol Cancer Res 3:503–509

    Article  CAS  PubMed  Google Scholar 

  54. Hiyama E, Gollahon L, Kataoka T, Kuroi K, Yokoyama T, Gazdar AF, Hiyama K, Piatyszek MA, Shay JW (1996) Telomerase activity in human breast tumors. J Natl Cancer Inst 88:116–122

    Article  CAS  PubMed  Google Scholar 

  55. Liu J, Baykal A, Fung KM, Thompson-Lanza JA, Hoque A, Lippman SM, Sahin A (2004) Human telomerase reverse transcriptase mRNA is highly expressed in normal breast tissues and down-regulated in ductal carcinoma in situ. Int J Oncol 24:879–884

    CAS  PubMed  Google Scholar 

  56. Kolquist KA, Ellisen LW, Counter CM, Meyerson M, Tan LK, Weinberg RA, Haber DA, Gerald WL (1998) Expression of TERT in early premalignant lesions and a subset of cells in normal tissues. Nat Genet 19:182–186

    Article  CAS  PubMed  Google Scholar 

  57. Kyo S, Takakura M, Fujiwara T, Inoue M (2008) Understanding and exploiting hTERT promoter regulation for diagnosis and treatment of human cancers. Cancer Sci 99:1528–1538

    Article  CAS  PubMed  Google Scholar 

  58. Sawyers CL (2008) The cancer biomarker problem. Nature 452:548–552

    Article  CAS  PubMed  Google Scholar 

  59. Paci E, Warwick J, Falini P, Duffy SW (2004) Overdiagnosis in screening: is the increase in breast cancer incidence rates a cause for concern? J Med Screen 11:23–27

    Article  CAS  PubMed  Google Scholar 

  60. Bernards R, Weinberg RA (2002) A progression puzzle. Nature 418:823

    Article  CAS  PubMed  Google Scholar 

  61. Cancer KleinCA (2008) The metastasis cascade. Science 321:1785–1787 New York, NY

    Article  Google Scholar 

  62. Robson ME (2007) Treatment of hereditary breast cancer. Semin Oncol 34:384–391

    Article  CAS  PubMed  Google Scholar 

  63. Celis JE, Moreira JM, Gromova I, Cabezon T, Ralfkiaer U, Guldberg P, Straten PT, Mouridsen H, Friis E, Holm D, Rank F, Gromov P (2005) Towards discovery-driven translational research in breast cancer. FEBS J 272:2–15

    Article  CAS  PubMed  Google Scholar 

  64. Ottewell PD, Coleman RE, Holen I (2006) From genetic abnormality to metastases: murine models of breast cancer and their use in the development of anticancer therapies. Breast Cancer Res Treat 96:101–113

    Article  CAS  PubMed  Google Scholar 

  65. Kuperwasser C, Chavarria T, Wu M, Magrane G, Gray JW, Carey L, Richardson A, Weinberg RA (2004) Reconstruction of functionally normal and malignant human breast tissues in mice. Proc Natl Acad Sci USA 101:4966–4971

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Affiliations

  1. Department of Pathology, The Johns Hopkins Medical Institutions, 411 N. Caroline St., Baltimore, MD, 21231, USA

    Christopher M. Heaphy

  2. Department of Biochemistry and Molecular Biology, University of New Mexico School of Medicine, MSC08 4670, 1 University of New Mexico, Albuquerque, NM, 87131-0001, USA

    Jeffrey K. Griffith & Marco Bisoffi

Authors
  1. Christopher M. Heaphy
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jeffrey K. Griffith
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Marco Bisoffi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Marco Bisoffi.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Heaphy, C.M., Griffith, J.K. & Bisoffi, M. Mammary field cancerization: molecular evidence and clinical importance. Breast Cancer Res Treat 118, 229–239 (2009). https://doi.org/10.1007/s10549-009-0504-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10549-009-0504-0

Keywords

  • Breast cancer field cancerization
  • Genomic instability
  • Epigenetics
  • Gene expression
  • Clinical importance