Top

Published in:

01-01-2010 | Preclinical Study

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

Authors: Dung-Tsa Chen, Aejaz Nasir, Aedin Culhane, Chinnambally Venkataramu, William Fulp, Renee Rubio, Tao Wang, Deepak Agrawal, Susan M. McCarthy, Mike Gruidl, Gregory Bloom, Tove Anderson, Joe White, John Quackenbush, Timothy Yeatman

Published in: Breast Cancer Research and Treatment | Issue 2/2010

Abstact

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.

Available only for authorised users

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 CrossRefPubMed

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 CrossRefPubMed

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):166–172PubMed

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 CrossRefPubMed

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 CrossRefPubMed

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 CrossRefPubMed

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 CrossRefPubMed

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):283–290PubMed

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):1000–1003PubMed

10.

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

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):1053–1055PubMed

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 CrossRefPubMed

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)

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 CrossRefPubMed

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 CrossRefPubMed

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 CrossRefPubMed

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 CrossRefPubMed

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 CrossRefPubMed

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 CrossRefPubMed

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 CrossRefPubMed

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 CrossRefPubMed

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 CrossRefPubMed

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 CrossRefPubMed

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):671–679PubMed

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 CrossRefPubMed

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 CrossRefPubMed

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):e15CrossRefPubMed

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 CrossRefPubMed

29.

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

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 CrossRefPubMed

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 CrossRefPubMed

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 CrossRefPubMed

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 CrossRefPubMed

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 CrossRefPubMed

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 CrossRefPubMed

Title: Proliferative genes dominate malignancy-risk gene signature in histologically-normal breast tissue
Authors: Dung-Tsa Chen
Aejaz Nasir
Aedin Culhane
Chinnambally Venkataramu
William Fulp
Renee Rubio
Tao Wang
Deepak Agrawal
Susan M. McCarthy
Mike Gruidl
Gregory Bloom
Tove Anderson
Joe White
John Quackenbush
Timothy Yeatman
Publication date: 01-01-2010
Publisher: Springer US
Published in: Breast Cancer Research and Treatment / Issue 2/2010
Print ISSN: 0167-6806
Electronic ISSN: 1573-7217
DOI: https://doi.org/10.1007/s10549-009-0344-y

Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras

Prof. Fabrice Barlesi

Developed by: Springer Medicine

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstact

Please log in to get access to this content

Other articles of this Issue 2/2010

Association between polymorphisms of XRCC1 and offspring sex ratio at births in families of female breast cancer patients

Identification and characterization of two novel germ line p53 mutations in the non-LFS/non-LFL breast cancer families in Chinese population

Soluble factors derived from tumor mammary cell lines induce a stromal mammary adipose reversion in human and mice adipose cells. Possible role of TGF-β1 and TNF-α

The impact of preoperative breast MRI on the re-excision rate in invasive lobular carcinoma of the breast

Relationship between oestrogen receptor status and proliferation in predicting response and long-term outcome to neoadjuvant chemotherapy for breast cancer

Are mammography recommendations in women younger than 40 related to increased risk?

Keynote webinar | Spotlight on antibody–drug conjugates in cancer