Breast Cancer Research and Treatment

, Volume 135, Issue 1, pp 115–124 | Cite as

Nuclear nano-morphology markers of histologically normal cells detect the “field effect” of breast cancer

  • Rajan K. Bista
  • Pin Wang
  • Rohit Bhargava
  • Shikhar Uttam
  • Douglas J. Hartman
  • Randall E. Brand
  • Yang Liu
Preclinical Study

Abstract

Accurate detection of breast malignancy from histologically normal cells (“field effect”) has significant clinical implications in a broad base of breast cancer management, such as high-risk lesion management, personalized risk assessment, breast tumor recurrence, and tumor margin management. More accurate and clinically applicable tools to detect markers characteristic of breast cancer “field effect” that are able to guide the clinical management are urgently needed. We have recently developed a novel optical microscope, spatial-domain low-coherence quantitative phase microscopy, which extracts the nanoscale structural characteristics of cell nuclei (i.e., nuclear nano-morphology markers), using standard histology slides. In this proof-of-concept study, we present the use of these highly sensitive nuclear nano-morphology markers to identify breast malignancy from histologically normal cells. We investigated the nano-morphology markers from 154 patients with a broad spectrum of breast pathology entities, including normal breast tissue, non-proliferative benign lesions, proliferative lesions (without and with atypia), “malignant-adjacent” normal tissue, and invasive carcinoma. Our results show that the nuclear nano-morphology markers of “malignant-adjacent” normal tissue can detect the presence of invasive breast carcinoma with high accuracy and do not reflect normal aging. Further, we found that a progressive change in nuclear nano-morphology markers that parallel breast cancer risk, suggesting its potential use for risk stratification. These novel nano-morphology markers that detect breast cancerous changes from nanoscale structural characteristics of histologically normal cells could potentially benefit the diagnosis, risk assessment, prognosis, prevention, and treatment of breast cancer.

Keywords

Field effect Nanoscale structure Phase microscopy Nuclear nano-morphology markers 

Notes

Acknowledgments

This study was supported by research grants from National Institute of Health (R21CA152935) and Wallace H. Coulter foundation. P. W. acknowledges the support from National Energy Technology Laboratory Research Participation Program sponsored by the U.S. Department of Energy and administered by the Oak Ridge Institute for Science and Education.

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

10549_2012_2125_MOESM1_ESM.doc (150 kb)
Supplementary material 1 (DOC 150 kb)

References

  1. 1.
    Kopelovich L, Henson DE, Gazdar AF, Dunn B, Srivastava S, Kelloff GJ, Greenwald P (1999) Surrogate anatomic/functional sites for evaluating cancer risk: an extension of the field effect. Clin Cancer Res 5(12):3899–3905PubMedGoogle Scholar
  2. 2.
    Slaughter DP, Southwick HW, Smejkal W (1953) Field cancerization in oral stratified squamous epithelium; clinical implications of multicentric origin. Cancer 6(5):963–968PubMedCrossRefGoogle Scholar
  3. 3.
    Heaphy CM, Griffith JK, Bisoffi M (2009) Mammary field cancerization: molecular evidence and clinical importance. Breast Cancer Res Treat 118(2):229–239. doi: 10.1007/s10549-009-0504-0 PubMedCrossRefGoogle Scholar
  4. 4.
    Chai H, Brown RE (2009) Field effect in cancer-an update. Ann Clin Lab Sci 39(4):331–337PubMedGoogle Scholar
  5. 5.
    Dakubo GD, Jakupciak JP, Birch-Machin MA, Parr RL (2007) Clinical implications and utility of field cancerization. Cancer Cell Int 7:2. doi: 10.1186/1475-2867-7-2 PubMedCrossRefGoogle Scholar
  6. 6.
    Deng G, Lu Y, Zlotnikov G, Thor AD, Smith HS (1996) Loss of heterozygosity in normal tissue adjacent to breast carcinomas. Science 274(5295):2057–2059PubMedCrossRefGoogle Scholar
  7. 7.
    Harada Y, Katagiri T, Ito I, Akiyama F, Sakamoto G, Kasumi F, Nakamura Y, Emi M (1994) Genetic studies of 457 breast cancers. Clinicopathologic parameters compared with genetic alterations. Cancer 74(8):2281–2286PubMedCrossRefGoogle Scholar
  8. 8.
    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(6):1591–1598PubMedGoogle Scholar
  9. 9.
    Fackenthal JD, Olopade OI (2007) Breast cancer risk associated with BRCA1 and BRCA2 in diverse populations. Nat Rev Cancer 7(12):937–948. doi: 10.1038/nrc2054 PubMedCrossRefGoogle Scholar
  10. 10.
    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(22):6626–6636. doi: 10.1158/1078-0432.CCR-06-0467 PubMedCrossRefGoogle Scholar
  11. 11.
    Dworkin AM, Huang TH, Toland AE (2009) Epigenetic alterations in the breast: implications for breast cancer detection, prognosis and treatment. Semin Cancer Biol 19(3):165–171. doi: 10.1016/j.semcancer.2009.02.007 PubMedCrossRefGoogle Scholar
  12. 12.
    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(1):166–172PubMedGoogle Scholar
  13. 13.
    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(1):108–116. doi: 10.1002/ijc.21815 PubMedCrossRefGoogle Scholar
  14. 14.
    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(2):182–186. doi: 10.1038/554 PubMedCrossRefGoogle Scholar
  15. 15.
    Backman V, Roy HK (2011) Light-scattering technologies for field carcinogenesis detection: a modality for endoscopic prescreening. Gastroenterology 140(1):35–41. doi: 10.1053/j.gastro.2010.11.023 PubMedCrossRefGoogle Scholar
  16. 16.
    Subramanian H, Pradhan P, Liu Y, Capoglu IR, Li X, Rogers JD, Heifetz A, Kunte D, Roy HK, Taflove A, Backman V (2008) Optical methodology for detecting histologically unapparent nanoscale consequences of genetic alterations in biological cells. Proc Natl Acad Sci USA 105(51):20118–20123. doi: 10.1073/pnas.0804723105 PubMedCrossRefGoogle Scholar
  17. 17.
    Subramanian H, Roy HK, Pradhan P, Goldberg MJ, Muldoon J, Brand RE, Sturgis C, Hensing T, Ray D, Bogojevic A, Mohammed J, Chang JS, Backman V (2009) Nanoscale cellular changes in field carcinogenesis detected by partial wave spectroscopy. Cancer Res 69(13):5357–5363. doi: 10.1158/0008-5472.CAN-08-3895 PubMedCrossRefGoogle Scholar
  18. 18.
    Roy HK, Subramanian H, Damania D, Hensing TA, Rom WN, Pass HI, Ray D, Rogers JD, Bogojevic A, Shah M, Kuzniar T, Pradhan P, Backman V (2010) Optical detection of buccal epithelial nanoarchitectural alterations in patients harboring lung cancer: implications for screening. Cancer Res 70(20):7748–7754. doi: 10.1158/0008-5472.CAN-10-1686 PubMedCrossRefGoogle Scholar
  19. 19.
    Roy HK, Hensing T, Backman V (2011) Nanocytology for field carcinogenesis detection: novel paradigm for lung cancer risk stratification. Future Oncol 7(1):1–3. doi: 10.2217/fon.10.176 PubMedCrossRefGoogle Scholar
  20. 20.
    Bista RK, Brentnall TA, Bronner MP, Langmead CJ, Brand RE, Liu Y (2011) Using optical markers of nondysplastic rectal epithelial cells to identify patients with ulcerative colitis-associated neoplasia. Inflamm Bowel Dis 17(12):2427–2435. doi: 10.1002/ibd.21639 PubMedCrossRefGoogle Scholar
  21. 21.
    Wang P, Bista R, Khalbuss WE, Qiu W, Staton K, Zhang L, Brentnall TA, Brand RE, Liu Y (2010) Nanoscale nuclear architecture for cancer diagnosis beyond pathology via spatial-domain low-coherence quantitative phase microscopy. J Biomed Opt 15:066028PubMedCrossRefGoogle Scholar
  22. 22.
    Wang P, Bista RK, Qiu W, Khalbuss WE, Zhang L, Brand RE, Liu Y (2010) An insight into statistical refractive index properties of cell internal structure via low-coherence statistical amplitude microscopy. Opt Express 18(21):21950–21958PubMedCrossRefGoogle Scholar
  23. 23.
    Wang P, Bista R, Bhargava R, Brand RE, Liu Y (2010) Spatial-domain low-coherence quantitative phase microscopy for cancer diagnosis. Opt Lett 35(17):2840–2842PubMedCrossRefGoogle Scholar
  24. 24.
    Uttam S, Bista RK, Hartman DJ, Brand RE, Liu Y (2011) Correction of stain variations in nuclear refractive index of clinical histology specimens. J Biomed Opt 16(11):116013. doi: 10.1117/1.3650306 PubMedCrossRefGoogle Scholar
  25. 25.
    Bista RK, Uttam S, Hartman DJ, Qiu W, Yu J, Zhang L, Brand RE, Liu, Y (2012) Investigation of nuclear nano-morphology marker as a biomarker for cancer risk assessment using a mouse model. J Biomed Opt 17(6):066014. doi: 10.1117/1.JBO.17.6.066014 Google Scholar
  26. 26.
    Gonen M (2007) Analyzing receiver operating characteristic curves with SAS. SAS Institute, CaryGoogle Scholar
  27. 27.
    Dupont WD, Page DL (1985) Risk factors for breast cancer in women with proliferative breast disease. N Engl J Med 312(3):146–151. doi: 10.1056/NEJM198501173120303 PubMedCrossRefGoogle Scholar
  28. 28.
    Hartmann LC, Sellers TA, Frost MH, Lingle WL, Degnim AC, Ghosh K, Vierkant RA, Maloney SD, Pankratz VS, Hillman DW, Suman VJ, Johnson J, Blake C, Tlsty T, Vachon CM, Melton LJ 3rd, Visscher DW (2005) Benign breast disease and the risk of breast cancer. N Engl J Med 353(3):229–237. doi: 10.1056/NEJMoa044383 PubMedCrossRefGoogle Scholar
  29. 29.
    Issa JP, Ottaviano YL, Celano P, Hamilton SR, Davidson NE, Baylin SB (1994) Methylation of the oestrogen receptor CpG island links ageing and neoplasia in human colon. Nat Genet 7(4):536–540. doi: 10.1038/ng0894-536 PubMedCrossRefGoogle Scholar
  30. 30.
    Issa JP (2002) Epigenetic variation and human disease. J Nutr 132(8 Suppl):2388S–2392SPubMedGoogle Scholar
  31. 31.
    Santen RJ, Mansel R (2005) Benign breast disorders. N Engl J Med 353(3):275–285. doi: 10.1056/NEJMra035692 PubMedCrossRefGoogle Scholar
  32. 32.
    Bista RK, Uttam S, Wang P, Staton K, Choi S, Bakkenist CJ, Hartman DJ, Brand RE, Liu Y (2011) Quantification of nanoscale nuclear refractive index changes during the cell cycle. J Biomed Opt 16(7):070503. doi: 10.1117/1.3597723 PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC. 2012

Authors and Affiliations

  • Rajan K. Bista
    • 1
  • Pin Wang
    • 1
  • Rohit Bhargava
    • 2
  • Shikhar Uttam
    • 1
  • Douglas J. Hartman
    • 3
  • Randall E. Brand
    • 1
  • Yang Liu
    • 1
    • 4
    • 5
  1. 1.Division of Gastroenterology, Hepatology and Nutrition, Department of MedicineUniversity of PittsburghPittsburghUSA
  2. 2.Department of Pathology, Magee-Womens HospitalUniversity of Pittsburgh Medical CenterPittsburghUSA
  3. 3.Department of PathologyUniversity of Pittsburgh School of MedicinePittsburghUSA
  4. 4.Department of BioengineeringUniversity of PittsburghPittsburghUSA
  5. 5.Departments of Medicine and BioengineeringUniversity of PittsburghPittsburghUSA

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