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Proliferative genes dominate malignancy-risk gene signature in histologically-normal breast tissue

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Historical data have indicated the potential for the histologically-normal breast to harbor pre-malignant changes at the molecular level. We postulated that a histologically-normal tissue with “tumor-like” gene expression pattern might harbor substantial risk for future cancer development. Genes associated with these high-risk tissues were considered to be “malignancy-risk genes”. From a total of 90 breast cancer patients, we collected a set of 143 histologically-normal breast tissues derived from patients harboring breast cancer who underwent curative mastectomy, as well as a set of 42 invasive ductal carcinomas (IDC) of various histologic grades. All samples were assessed for global gene expression differences using microarray analysis. For the purpose of this study we defined normal breast tissue to include histologically normal and benign lesions. Here we report the discovery of a “malignancy-risk” gene signature that may portend risk of breast cancer development in benign, but molecularly-abnormal, breast tissue. Pathway analysis showed that the malignancy-risk signature had a dramatic enrichment for genes with proliferative function, but appears to be independent of ER, PR, and HER2 status. The signature was validated by RT-PCR, with a high correlation (Pearson correlation = 0.95 with P < 0.0001) with microarray data. These results suggest a predictive role for the malignancy-risk signature in normal breast tissue. Proliferative biology dominates the earliest stages of tumor development.

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References

  1. Berry DA, Cronin KA, Plevritis SK, Fryback DG, Clarke L, Zelen M et al (2005) Effect of screening and adjuvant therapy on mortality from breast cancer. N Engl J Med 353(17):1784–1792. doi:10.1056/NEJMoa050518

    Article  PubMed  CAS  Google Scholar 

  2. Giordano SH, Buzdar AU, Smith TL, Kau SW, Yang Y, Hortobagyi GN (2004) Is breast cancer survival improving? Cancer 100(1):44–52. doi:10.1002/cncr.11859

    Article  PubMed  Google Scholar 

  3. Lewis CM, Cler LR, Bu DW, Zochbauer-Muller S, Milchgrub S, Naftalis EZ et al (2005) Promoter hypermethylation in benign breast epithelium in relation to predicted breast cancer risk. Clin Cancer Res 11(1):166–172

    PubMed  CAS  Google Scholar 

  4. Deng GR, Lu Y, Zlotnikov G, Thor AD, Smith HS (1996) Loss of heterozygosity in normal tissue adjacent to breast carcinomas. Science 274(5295):2057–2059. doi:10.1126/science.274.5295.2057

    Article  PubMed  CAS  Google Scholar 

  5. Fredriksson I, Liljegren G, Palm-Sjovall M, Arnesson LG, Emdin SO, Fornander T et al (2003) Risk factors for local recurrence after breast-conserving surgery. Br J Surg 90(9):1093–1102. doi:10.1002/bjs.4206

    Article  PubMed  CAS  Google Scholar 

  6. Ellsworth DL, Ellsworth RE, Love B, Deyarmin B, Lubert SM, Mittal V et al (2004) Outer breast quadrants demonstrate increased levels of genomic instability. Ann Surg Oncol 11(9):861–868. doi:10.1245/ASO.2004.03.024

    Article  PubMed  Google Scholar 

  7. Botti C, Pescatore B, Mottolese M, Sciarretta F, Greco C, Di Filippo F et al (2000) Incidence of chromosomes 1 and 17 aneusomy in breast cancer and adjacent tissue: an interphase cytogenetic study. J Am Coll Surg 190(5):530–539. doi:10.1016/S1072-7515(00)00252-0

    Article  PubMed  CAS  Google Scholar 

  8. 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(1):283–290

    PubMed  Google Scholar 

  9. Li Z, Moore DH, Meng ZH, Ljung BM, Gray JW, Dairkee SH (2002) Increased risk of local recurrence is associated with allelic loss in normal lobules of breast cancer patients. Cancer Res 62(4):1000–1003

    PubMed  CAS  Google Scholar 

  10. Schnitt SJ, Morrow M (1999) Lobular carcinoma in situ: current concepts and controversies. Semin Diagn Pathol 16(3):209–223

    PubMed  CAS  Google Scholar 

  11. Fitzgibbons PL, DE Henson, Hutter RV (1998) Benign breast changes and the risk for subsequent breast cancer: an update of the 1985 consensus statement. Cancer Committee of the College of American Pathologists. Arch Pathol Lab Med 122(12):1053–1055

    PubMed  CAS  Google Scholar 

  12. Wapnir IL, Anderson SJ, Mamounas EP, Geyer CE Jr, Jeong JH, Tan-Chiu E et al (2006) Prognosis after ipsilateral breast tumor recurrence and locoregional recurrences in five National Surgical Adjuvant Breast and Bowel Project node-positive adjuvant breast cancer trials. J Clin Oncol 24(13):2028–2037. doi:10.1200/JCO.2005.04.3273

    Article  PubMed  Google Scholar 

  13. Wapnir I, Anderson SEM, Mamounas E et al (2005) Survival after IBTR in NSABP Node Negative Protocols B-13, B-14, B-19, B-20 and B-23. J Clin Oncol 23:8s (suppl; abstr 517)

    Google Scholar 

  14. Carter SL, Eklund AC, Kohane IS, Harris LN, Szallasi Z (2006) A signature of chromosomal instability inferred from gene expression profiles predicts clinical outcome in multiple human cancers. Nat Genet 38(9):1043–1048. doi:10.1038/ng1861

    Article  PubMed  CAS  Google Scholar 

  15. Chang HY, Nuyten DS, Sneddon JB, Hastie T, Tibshirani R, Sorlie T et al (2005) Robustness, scalability, and integration of a wound-response gene expression signature in predicting breast cancer survival. Proc Natl Acad Sci USA 102(10):3738–3743. doi:10.1073/pnas.0409462102

    Article  PubMed  CAS  Google Scholar 

  16. Finak G, Bertos N, Pepin F, Sadekova S, Souleimanova M, Zhao H et al (2008) Stromal gene expression predicts clinical outcome in breast cancer. Nat Med 14(5):518–527. doi:10.1038/nm1764

    Article  PubMed  CAS  Google Scholar 

  17. Glas AM, Floore A, Delahaye LJ, Witteveen AT, Pover RC, Bakx N et al (2006) Converting a breast cancer microarray signature into a high-throughput diagnostic test. BMC Genomics 7:278. doi:10.1186/1471-2164-7-278

    Article  PubMed  CAS  Google Scholar 

  18. Huang E, Cheng SH, Dressman H, Pittman J, Tsou MH, Horng CF et al (2003) Gene expression predictors of breast cancer outcomes. Lancet 361(9369):1590–1596. doi:10.1016/S0140-6736(03)13308-9

    Article  PubMed  CAS  Google Scholar 

  19. Ma XJ, Salunga R, Tuggle JT, Gaudet J, Enright E, McQuary P et al (2003) Gene expression profiles of human breast cancer progression. Proc Natl Acad Sci USA 100(10):5974–5979. doi:10.1073/pnas.0931261100

    Article  PubMed  CAS  Google Scholar 

  20. Paik S, Shak S, Tang G, Kim C, Baker J, Cronin M et al (2004) A multigene assay to predict recurrence of tamoxifen-treated, node-negative breast cancer. N Engl J Med 351(27):2817–2826. doi:10.1056/NEJMoa041588

    Article  PubMed  CAS  Google Scholar 

  21. Perou CM, Sorlie T, Eisen MB, van de Rijn M, Jeffrey SS, Rees CA et al (2000) Molecular portraits of human breast tumours. Nature 406(6797):747–752. doi:10.1038/35021093

    Article  PubMed  CAS  Google Scholar 

  22. Sorlie T, Perou CM, Tibshirani R, Aas T, Geisler S, Johnsen H et al (2001) Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc Natl Acad Sci USA 98(19):10869–10874. doi:10.1073/pnas.191367098

    Article  PubMed  CAS  Google Scholar 

  23. van de Vijver MJ, He YD, van ‘t Veer LJ, Dai H, Hart AAM, Voskuil DW et al (2002) A gene-expression signature as a predictor of survival in breast cancer. N Engl J Med 347(25):1999–2009. doi:10.1056/NEJMoa021967

    Article  PubMed  Google Scholar 

  24. Wang Y, Klijn JG, Zhang Y, Sieuwerts AM, Look MP, Yang F et al (2005) Gene-expression profiles to predict distant metastasis of lymph-node-negative primary breast cancer. Lancet 365(9460):671–679

    PubMed  CAS  Google Scholar 

  25. Shah VI, Raju U, Chitale D, Deshpande V, Gregory N, Strand V (2003) False-negative core needle biopsies of the breast—an analysis of clinical, radiologic, and pathologic findings in 27 consecutive cases of missed breast cancer. Cancer 97(8):1824–1831. doi:10.1002/cncr.11278

    Article  PubMed  Google Scholar 

  26. Robbins P, Pinder S, Deklerk N, Dawkins H, Harvey J, Sterrett G et al (1995) Histological grading of breast carcinomas—a study of interobserver agreement. Hum Pathol 26(8):873–879. doi:10.1016/0046-8177(95)90010-1

    Article  PubMed  CAS  Google Scholar 

  27. Irizarry RA, Bolstad BM, Collin F, Cope LM, Hobbs B, Speed TP (2003) Summaries of Affymetrix GeneChip probe level data. Nucleic Acids Res 31(4):e15

    Article  PubMed  CAS  Google Scholar 

  28. Tusher VG, Tibshirani R, Chu G (2001) Significance analysis of microarrays applied to the ionizing radiation response. Proc Natl Acad Sci USA 98(9):5116–5121. doi:10.1073/pnas.091062498

    Article  PubMed  CAS  Google Scholar 

  29. Miller RG (1981) Simultaneous statistical inference, 2nd edn. Springer-Verlag, New York, NY

    Google Scholar 

  30. Whitfield ML, Sherlock G, Saldanha AJ, Murray JI, Ball CA, Alexander KE et al (2002) Identification of genes periodically expressed in the human cell cycle and their expression in tumors. Mol Biol Cell 13(6):1977–2000. doi:10.1091/mbc.02-02-0030

    Article  PubMed  CAS  Google Scholar 

  31. Poola I, DeWitty RL, Marshalleck JJ, Bhatnagar R, Abraham J, Leffall LD (2005) Identification of MMP-1 as a putative breast cancer predictive marker by global gene expression analysis. Nat Med 11(5):481–483. doi:10.1038/nm1243

    Article  PubMed  CAS  Google Scholar 

  32. Rosenwald A, Wright G, Wiestner A, Chan WC, Connors JM, Campo E et al (2003) The proliferation gene expression signature is a quantitative integrator of oncogenic events that predicts survival in mantle cell lymphoma. Cancer Cell 3(2):185–197. doi:10.1016/S1535-6108(03)00028-X

    Article  PubMed  CAS  Google Scholar 

  33. Whitfield ML, George LK, Grant GD, Perou CM (2006) Common markers of proliferation. Nat Rev Cancer 6(2):99–106. doi:10.1038/nrc1802

    Article  PubMed  CAS  Google Scholar 

  34. Chung CH, Bernard PS, Perou CM (2002) Molecular portraits and the family tree of cancer. Nat Genet 32(Suppl):533–540. doi:10.1038/ng1038

    Article  PubMed  CAS  Google Scholar 

  35. Tripathi A, King C, de la Morenas A, Perry VK, Burke B, Antoine GA et al (2008) Gene expression abnormalities in histologically normal breast epithelium of breast cancer patients. Int J Cancer 122(7):1557–1566. doi:10.1002/ijc.23267

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This Research is funded by National Cancer Institute grant R01CA112215 (PI: TJY) and National Cancer Institute Grant R01 CA 098522(PI: TJY). We thank Magaly Mendez for assistance in manuscript preparation, the Histology Core for the technical support, and Drs. Khakpour, McBride, and Yamauchi for helpful discussion. The authors gratefully acknowledge the helpful comments by anonymous referees

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Authors and Affiliations

  1. Biostatistics Department, Moffitt Cancer Center & Research Institute, Tampa, FL, 33612, USA

    Dung-Tsa Chen & William Fulp

  2. Pathology, Moffitt Cancer Center & Research Institute, Tampa, FL, 33612, USA

    Aejaz Nasir

  3. Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA, 02115, USA

    Aedin Culhane, Renee Rubio, Tove Anderson, Joe White & John Quackenbush

  4. Department of Epidemiology and Biostatistics, University of South Florida, Tampa, FL, 33612, USA

    Tao Wang

  5. Molecular Oncology, Moffitt Cancer Center & Research Institute, Tampa, FL, 33612, USA

    Chinnambally Venkataramu, Deepak Agrawal, Susan M. McCarthy & Mike Gruidl

  6. Biomedical Informatics Department, Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA

    Gregory Bloom

  7. Surgery and Interdisciplinary Oncology, Moffitt Cancer Center & Research Institute, Tampa, FL, 33612, USA

    Timothy Yeatman

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  1. Dung-Tsa Chen
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Correspondence to Timothy Yeatman.

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Aejaz Nasir is a joining first author.

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Chen, DT., Nasir, A., Culhane, A. et al. Proliferative genes dominate malignancy-risk gene signature in histologically-normal breast tissue. Breast Cancer Res Treat 119, 335–346 (2010). https://doi.org/10.1007/s10549-009-0344-y

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  • DOI: https://doi.org/10.1007/s10549-009-0344-y

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