Skip to main content

Advertisement

SpringerLink
Log in

Characterizing the heterogeneity of triple-negative breast cancers using microdissected normal ductal epithelium and RNA-sequencing

  • Preclinical study
  • Published:
Breast Cancer Research and Treatment Aims and scope Submit manuscript

Abstract

Triple-negative breast cancers (TNBCs) are a heterogeneous set of tumors defined by an absence of actionable therapeutic targets (ER, PR, and HER-2). Microdissected normal ductal epithelium from healthy volunteers represents a novel comparator to reveal insights into TNBC heterogeneity and to inform drug development. Using RNA-sequencing data from our institution and The Cancer Genome Atlas (TCGA) we compared the transcriptomes of 94 TNBCs, 20 microdissected normal breast tissues from healthy volunteers from the Susan G. Komen for the Cure Tissue Bank, and 10 histologically normal tissues adjacent to tumor. Pathway analysis comparing TNBCs to optimized normal controls of microdissected normal epithelium versus classic controls composed of adjacent normal tissue revealed distinct molecular signatures. Differential gene expression of TNBC compared with normal comparators demonstrated important findings for TNBC-specific clinical trials testing targeted agents; lack of over-expression for negative studies and over-expression in studies with drug activity. Next, by comparing each individual TNBC to the set of microdissected normals, we demonstrate that TNBC heterogeneity is attributable to transcriptional chaos, is associated with non-silent DNA mutational load, and explains transcriptional heterogeneity in addition to known molecular subtypes. Finally, chaos analysis identified 146 core genes dysregulated in >90 % of TNBCs revealing an over-expressed central network. In conclusion, use of microdissected normal ductal epithelium from healthy volunteers enables an optimized approach for studying TNBC and uncovers biological heterogeneity mediated by transcriptional chaos.

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

Access this article

Log in via an institution

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

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Schneider BP, Winer EP, Foulkes WD, Garber J, Perou CM, Richardson A, Sledge GW, Carey LA (2008) Triple-negative breast cancer: risk factors to potential targets. Clin Cancer Res 14(24):8010–8018. doi:10.1158/1078-0432.CCR-08-1208

    Article  CAS  PubMed  Google Scholar 

  2. Dent R, Trudeau M, Pritchard KI, Hanna WM, Kahn HK, Sawka CA, Lickley LA, Rawlinson E, Sun P, Narod SA (2007) Triple-negative breast cancer: clinical features and patterns of recurrence. Clin Cancer Res 13(15 Pt 1):4429–4434. doi:10.1158/1078-0432.CCR-06-3045

    Article  PubMed  Google Scholar 

  3. Carey LA, Perou CM, Livasy CA, Dressler LG, Cowan D, Conway K, Karaca G, Troester MA, Tse CK, Edmiston S, Deming SL, Geradts J, Cheang MC, Nielsen TO, Moorman PG, Earp HS, Millikan RC (2006) Race, breast cancer subtypes, and survival in the Carolina Breast Cancer Study. JAMA 295(21):2492–2502. doi:10.1001/jama.295.21.2492

    Article  CAS  PubMed  Google Scholar 

  4. Stark A, Kleer CG, Martin I, Awuah B, Nsiah-Asare A, Takyi V, Braman M, Quayson SE, Zarbo R, Wicha M, Newman L (2010) African ancestry and higher prevalence of triple-negative breast cancer: findings from an international study. Cancer 116(21):4926–4932. doi:10.1002/cncr.25276

    Article  PubMed Central  PubMed  Google Scholar 

  5. Huo D, Ikpatt F, Khramtsov A, Dangou JM, Nanda R, Dignam J, Zhang B, Grushko T, Zhang C, Oluwasola O, Malaka D, Malami S, Odetunde A, Adeoye AO, Iyare F, Falusi A, Perou CM, Olopade OI (2009) Population differences in breast cancer: survey in indigenous African women reveals over-representation of triple-negative breast cancer. J Clin Oncol 27(27):4515–4521. doi:10.1200/JCO.2008.19.6873

    Article  CAS  PubMed  Google Scholar 

  6. Ambaye AB, MacLennan SE, Goodwin AJ, Suppan T, Naud S, Weaver DL (2009) Carcinoma and atypical hyperplasia in reduction mammaplasty: increased sampling leads to increased detection. A prospective study. Plast Reconstr Surg 124(5):1386–1392. doi:10.1097/PRS.0b013e3181b988da

    Article  CAS  PubMed  Google Scholar 

  7. Ishag MT, Bashinsky DY, Beliaeva IV, Niemann TH, Marsh WL Jr (2003) Pathologic findings in reduction mammaplasty specimens. Am J Clin Pathol 120(3):377–380. doi:10.1309/4KD6-52HN-739X-TLM3

    Article  PubMed  Google Scholar 

  8. Ramakrishnan R, Bhandare D, Fine N, Khan SA, Lal A, Nayar R (2005) Pathologic findings in contralateral reduction mammaplasty specimens in patients with breast cancer. Breast J 11(5):372–373. doi:10.1111/j.1075-122X.2005.00059.x

    Article  PubMed  Google Scholar 

  9. Degnim AC, Visscher DW, Hoskin TL, Frost MH, Vierkant RA, Vachon CM, Shane Pankratz V, Radisky DC, Hartmann LC (2012) Histologic findings in normal breast tissues: comparison to reduction mammaplasty and benign breast disease tissues. Breast Cancer Res Treat 133(1):169–177. doi:10.1007/s10549-011-1746-1

    Article  PubMed Central  PubMed  Google Scholar 

  10. 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(7):1557–1566. doi:10.1002/ijc.23267

    Article  CAS  PubMed  Google Scholar 

  11. Graham K, Ge X, de Las Morenas A, Tripathi A, Rosenberg CL (2011) Gene expression profiles of estrogen receptor-positive and estrogen receptor-negative breast cancers are detectable in histologically normal breast epithelium. Clin Cancer Res 17(2):236–246. doi:10.1158/1078-0432.CCR-10-1369

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  12. 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

    Article  CAS  PubMed  Google Scholar 

  13. Deng G, Lu Y, Zlotnikov G, Thor AD, Smith HS (1996) Loss of heterozygosity in normal tissue adjacent to breast carcinomas. Science 274(5295):2057–2059

    Article  CAS  PubMed  Google Scholar 

  14. Lakhani SR, Chaggar R, Davies S, Jones C, Collins N, Odel C, Stratton MR, O’Hare MJ (1999) Genetic alterations in ‘normal’ luminal and myoepithelial cells of the breast. J Pathol 189(4):496–503. doi:10.1002/(SICI)1096-9896(199912)189:4<496:AID-PATH485>3.0.CO;2-D

    Article  CAS  PubMed  Google Scholar 

  15. Lehmann BD, Bauer JA, Chen X, Sanders ME, Chakravarthy AB, Shyr Y, Pietenpol JA (2011) Identification of human triple-negative breast cancer subtypes and preclinical models for selection of targeted therapies. J Clin Invest 121(7):2750–2767. doi:10.1172/JCI45014

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  16. Shah SP, Roth A, Goya R, Oloumi A, Ha G, Zhao Y, Turashvili G, Ding J, Tse K, Haffari G, Bashashati A, Prentice LM, Khattra J, Burleigh A, Yap D, Bernard V, McPherson A, Shumansky K, Crisan A, Giuliany R, Heravi-Moussavi A, Rosner J, Lai D, Birol I, Varhol R, Tam A, Dhalla N, Zeng T, Ma K, Chan SK, Griffith M, Moradian A, Cheng SW, Morin GB, Watson P, Gelmon K, Chia S, Chin SF, Curtis C, Rueda OM, Pharoah PD, Damaraju S, Mackey J, Hoon K, Harkins T, Tadigotla V, Sigaroudinia M, Gascard P, Tlsty T, Costello JF, Meyer IM, Eaves CJ, Wasserman WW, Jones S, Huntsman D, Hirst M, Caldas C, Marra MA, Aparicio S (2012) The clonal and mutational evolution spectrum of primary triple-negative breast cancers. Nature 486(7403):395–399. doi:10.1038/nature10933

    CAS  PubMed  Google Scholar 

  17. Cancer Genome Atlas Network (2012) Comprehensive molecular portraits of human breast tumours. Nature 490(7418):61–70. doi:10.1038/nature11412

    Article  Google Scholar 

  18. Herschkowitz JI, He X, Fan C, Perou CM (2008) The functional loss of the retinoblastoma tumour suppressor is a common event in basal-like and luminal B breast carcinomas. Breast Cancer Res 10(5):R75. doi:10.1186/bcr2142

    Article  PubMed Central  PubMed  Google Scholar 

  19. Curtis C, Shah SP, Chin SF, Turashvili G, Rueda OM, Dunning MJ, Speed D, Lynch AG, Samarajiwa S, Yuan Y, Graf S, Ha G, Haffari G, Bashashati A, Russell R, McKinney S, Langerod A, Green A, Provenzano E, Wishart G, Pinder S, Watson P, Markowetz F, Murphy L, Ellis I, Purushotham A, Borresen-Dale AL, Brenton JD, Tavare S, Caldas C, Aparicio S (2012) The genomic and transcriptomic architecture of 2,000 breast tumours reveals novel subgroups. Nature 486(7403):346–352. doi:10.1038/nature10983

    CAS  PubMed Central  PubMed  Google Scholar 

  20. Dawson SJ, Rueda OM, Aparicio S, Caldas C (2013) A new genome-driven integrated classification of breast cancer and its implications. EMBO J 32(5):617–628. doi:10.1038/emboj.2013.19

    Article  CAS  PubMed  Google Scholar 

  21. Sakarya O, Breu H, Radovich M, Chen Y, Wang YN, Barbacioru C, Utiramerur S, Whitley PP, Brockman JP, Vatta P, Zhang Z, Popescu L, Muller MW, Kudlingar V, Garg N, Li CY, Kong BS, Bodeau JP, Nutter RC, Gu J, Bramlett KS, Ichikawa JK, Hyland FC, Siddiqui AS (2012) RNA-Seq mapping and detection of gene fusions with a suffix array algorithm. PLoS Comput Biol 8(4):e1002464. doi:10.1371/journal.pcbi.1002464

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  22. Foulkes WD, Smith IE, Reis-Filho JS (2010) Triple-negative breast cancer. N Engl J Med 363(20):1938–1948. doi:10.1056/NEJMra1001389

    Article  CAS  PubMed  Google Scholar 

  23. Nielsen TO, Hsu FD, Jensen K, Cheang M, Karaca G, Hu Z, Hernandez-Boussard T, Livasy C, Cowan D, Dressler L, Akslen LA, Ragaz J, Gown AM, Gilks CB, van de Rijn M, Perou CM (2004) Immunohistochemical and clinical characterization of the basal-like subtype of invasive breast carcinoma. Clin Cancer Res 10(16):5367–5374. doi:10.1158/1078-0432.CCR-04-0220

    Article  CAS  PubMed  Google Scholar 

  24. Baselga J, Gomez P, Greil R, Braga S, Climent MA, Wardley AM, Kaufman B, Stemmer SM, Pego A, Chan A, Goeminne JC, Graas MP, Kennedy MJ, Ciruelos Gil EM, Schneeweiss A, Zubel A, Groos J, Melezinkova H, Awada A (2013) Randomized phase II study of the anti-epidermal growth factor receptor monoclonal antibody cetuximab with cisplatin versus cisplatin alone in patients with metastatic triple-negative breast cancer. J Clin Oncol. doi:10.1200/JCO.2012.46.2408

    Google Scholar 

  25. Baselga J, Albanell J, Ruiz A, Lluch A, Gascon P, Guillem V, Gonzalez S, Sauleda S, Marimon I, Tabernero JM, Koehler MT, Rojo F (2005) Phase II and tumor pharmacodynamic study of gefitinib in patients with advanced breast cancer. J Clin Oncol 23(23):5323–5333. doi:10.1200/JCO.2005.08.326

    Article  CAS  PubMed  Google Scholar 

  26. Modi S, Seidman AD, Dickler M, Moasser M, D’Andrea G, Moynahan ME, Menell J, Panageas KS, Tan LK, Norton L, Hudis CA (2005) A phase II trial of imatinib mesylate monotherapy in patients with metastatic breast cancer. Breast Cancer Res Treat 90(2):157–163. doi:10.1007/s10549-004-3974-0

    Article  CAS  PubMed  Google Scholar 

  27. Finn RS, Bengala C, Ibrahim N, Roche H, Sparano J, Strauss LC, Fairchild J, Sy O, Goldstein LJ (2011) Dasatinib as a single agent in triple-negative breast cancer: results of an open-label phase 2 study. Clin Cancer Res 17(21):6905–6913. doi:10.1158/1078-0432.CCR-11-0288

    Article  CAS  PubMed  Google Scholar 

  28. Carey LA, Rugo HS, Marcom PK, Mayer EL, Esteva FJ, Ma CX, Liu MC, Storniolo AM, Rimawi MF, Forero-Torres A, Wolff AC, Hobday TJ, Ivanova A, Chiu WK, Ferraro M, Burrows E, Bernard PS, Hoadley KA, Perou CM, Winer EP (2012) TBCRC 001: randomized phase II study of cetuximab in combination with carboplatin in stage IV triple-negative breast cancer. J Clin Oncol 30(21):2615–2623. doi:10.1200/JCO.2010.34.5579

    Article  CAS  PubMed  Google Scholar 

  29. Barretina J, Caponigro G, Stransky N, Venkatesan K, Margolin AA, Kim S, Wilson CJ, Lehar J, Kryukov GV, Sonkin D, Reddy A, Liu M, Murray L, Berger MF, Monahan JE, Morais P, Meltzer J, Korejwa A, Jane-Valbuena J, Mapa FA, Thibault J, Bric-Furlong E, Raman P, Shipway A, Engels IH, Cheng J, Yu GK, Yu J, Aspesi P Jr, de Silva M, Jagtap K, Jones MD, Wang L, Hatton C, Palescandolo E, Gupta S, Mahan S, Sougnez C, Onofrio RC, Liefeld T, MacConaill L, Winckler W, Reich M, Li N, Mesirov JP, Gabriel SB, Getz G, Ardlie K, Chan V, Myer VE, Weber BL, Porter J, Warmuth M, Finan P, Harris JL, Meyerson M, Golub TR, Morrissey MP, Sellers WR, Schlegel R, Garraway LA (2012) The cancer cell line encyclopedia enables predictive modelling of anticancer drug sensitivity. Nature 483(7391):603–607. doi:10.1038/nature11003

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  30. Broad Institute TCGA Genome Data Analysis Center (2013) Breast invasive carcinoma (primary solid tumor cohort)—21 April 2013: mutation analysis (MutSig v2.0). Broad Institute of MIT and Harvard. doi:10.7908/C1JS9NC5

  31. Cerami E, Gao J, Dogrusoz U, Gross BE, Sumer SO, Aksoy BA, Jacobsen A, Byrne CJ, Heuer ML, Larsson E, Antipin Y, Reva B, Goldberg AP, Sander C, Schultz N (2012) The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data. Cancer Discov 2(5):401–404. doi:10.1158/2159-8290.CD-12-0095

    Article  PubMed  Google Scholar 

  32. Gao J, Aksoy BA, Dogrusoz U, Dresdner G, Gross B, Sumer SO, Sun Y, Jacobsen A, Sinha R, Larsson E, Cerami E, Sander C, Schultz N (2013) Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Sci Signal 6(269):pl1. doi:10.1126/scisignal.2004088

    Article  CAS  PubMed  Google Scholar 

  33. Haibe-Kains B, Schroeder M, Bontempi G, Sotiriou C, Quackenbush J (2012) genefu: relevant functions for gene expression analysis, especially in breast cancer. R package version 191. http://compbio.dfci.harvard.edu

  34. Parker JS, Mullins M, Cheang MC, Leung S, Voduc D, Vickery T, Davies S, Fauron C, He X, Hu Z, Quackenbush JF, Stijleman IJ, Palazzo J, Marron JS, Nobel AB, Mardis E, Nielsen TO, Ellis MJ, Perou CM, Bernard PS (2009) Supervised risk predictor of breast cancer based on intrinsic subtypes. J Clin Oncol 27(8):1160–1167. doi:10.1200/JCO.2008.18.1370

    Article  PubMed  Google Scholar 

  35. 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

    Article  PubMed  Google Scholar 

  36. Trujillo KA, Heaphy CM, Mai M, Vargas KM, Jones AC, Vo P, Butler KS, Joste NE, Bisoffi M, Griffith JK (2011) Markers of fibrosis and epithelial to mesenchymal transition demonstrate field cancerization in histologically normal tissue adjacent to breast tumors. Int J Cancer 129(6):1310–1321. doi:10.1002/ijc.25788

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  37. Troester MA, Lee MH, Carter M, Fan C, Cowan DW, Perez ER, Pirone JR, Perou CM, Jerry DJ, Schneider SS (2009) Activation of host wound responses in breast cancer microenvironment. Clin Cancer Res 15(22):7020–7028. doi:10.1158/1078-0432.CCR-09-1126

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  38. Roman-Perez E, Casbas-Hernandez P, Pirone JR, Rein J, Carey LA, Lubet RA, Mani SA, Amos KD, Troester MA (2012) Gene expression in extratumoral microenvironment predicts clinical outcome in breast cancer patients. Breast Cancer Res 14(2):R51. doi:10.1186/bcr3152

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  39. Wang J, Scholtens D, Holko M, Ivancic D, Lee O, Hu H, Chatterton RT Jr, Sullivan ME, Hansen N, Bethke K, Zalles CM, Khan SA (2013) Lipid metabolism genes in contralateral unaffected breast and estrogen receptor status of breast cancer. Cancer Prev Res (Phila) 6(4):321–330. doi:10.1158/1940-6207.CAPR-12-0304

    Article  CAS  Google Scholar 

  40. Muenst S, Soysal SD, Gao F, Obermann EC, Oertli D, Gillanders WE (2013) The presence of programmed death 1 (PD-1)-positive tumor-infiltrating lymphocytes is associated with poor prognosis in human breast cancer. Breast Cancer Res Treat 139(3):667–676. doi:10.1007/s10549-013-2581-3

    Article  CAS  PubMed  Google Scholar 

  41. Komatsu M, Yoshimaru T, Matsuo T, Kiyotani K, Miyoshi Y, Tanahashi T, Rokutan K, Yamaguchi R, Saito A, Imoto S, Miyano S, Nakamura Y, Sasa M, Shimada M, Katagiri T (2013) Molecular features of triple negative breast cancer cells by genome-wide gene expression profiling analysis. Int J Oncol 42(2):478–506. doi:10.3892/ijo 2012.1744

    CAS  PubMed  Google Scholar 

  42. Sorlie T, Perou CM, Tibshirani R, Aas T, Geisler S, Johnsen H, Hastie T, Eisen MB, van de Rijn M, Jeffrey SS, Thorsen T, Quist H, Matese JC, Brown PO, Botstein D, Eystein Lonning P, Borresen-Dale 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  CAS  PubMed  Google Scholar 

  43. Perou CM, Sorlie T, Eisen MB, van de Rijn M, Jeffrey SS, Rees CA, Pollack JR, Ross DT, Johnsen H, Akslen LA, Fluge O, Pergamenschikov A, Williams C, Zhu SX, Lonning PE, Borresen-Dale AL, Brown PO, Botstein D (2000) Molecular portraits of human breast tumours. Nature 406(6797):747–752. doi:10.1038/35021093

    Article  CAS  PubMed  Google Scholar 

  44. O’Shaughnessy J, Osborne C, Pippen JE, Yoffe M, Patt D, Rocha C, Koo IC, Sherman BM, Bradley C (2011) Iniparib plus chemotherapy in metastatic triple-negative breast cancer. N Engl J Med 364(3):205–214. doi:10.1056/NEJMoa1011418

    Article  PubMed  Google Scholar 

  45. O’Shaughnessy J, Schwartzberg LS, Danso MA, Rugo HS, Miller K, Yardley DA, Carlson RW, Finn RS, Charpentier E, Freese M, Gupta S, Blackwood-Chirchir A, Winer EP (2011) A randomized phase III study of iniparib (BSI-201) in combination with gemcitabine/carboplatin (G/C) in metastatic triple-negative breast cancer (TNBC). J Clin Oncol (Meeting Abstracts) 29 (15):suppl; abstr 1007

    Google Scholar 

  46. Puhalla SL, Appleman LJ, Beumer JH, Tawbi H, Stoller RG, Owonikoko TK, Ramalingam SS, Belani CP, Brufsky AM, Abraham J, Shephard SP, Giranda V, Chen AP, Chu E (2012) Two phase I trials exploring different dosing schedules of carboplatin (C), paclitaxel (P), and the poly-ADP-ribose polymerase (PARP) inhibitor, veliparib (ABT-888) (V) with activity in triple negative breast cancer (TNBC). San Antonio breast cancer symposium poster discussion

  47. Fong PC, Boss DS, Yap TA, Tutt A, Wu P, Mergui-Roelvink M, Mortimer P, Swaisland H, Lau A, O’Connor MJ, Ashworth A, Carmichael J, Kaye SB, Schellens JH, de Bono JS (2009) Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. N Engl J Med 361(2):123–134. doi:10.1056/NEJMoa0900212

    Article  CAS  PubMed  Google Scholar 

  48. Tutt A, Robson M, Garber JE, Domchek SM, Audeh MW, Weitzel JN, Friedlander M, Arun B, Loman N, Schmutzler RK, Wardley A, Mitchell G, Earl H, Wickens M, Carmichael J (2010) Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and advanced breast cancer: a proof-of-concept trial. Lancet 376(9737):235–244. doi:10.1016/S0140-6736(10)60892-6

    Article  CAS  PubMed  Google Scholar 

  49. Wierstra I, Alves J (2007) FOXM1, a typical proliferation-associated transcription factor. Biol Chem 388(12):1257–1274. doi:10.1515/BC.2007.159

    Article  CAS  PubMed  Google Scholar 

  50. Raychaudhuri P, Park HJ (2011) FoxM1: a master regulator of tumor metastasis. Cancer Res 71(13):4329–4333. doi:10.1158/0008-5472.CAN-11-0640

    Article  CAS  PubMed Central  PubMed  Google Scholar 

Download references

Acknowledgments

We would like to thank Mark Mooney, James Elliott, Darryl Leon, and Ryan Richt for discussions of next-generation sequencing and analysis. We also like to thank Benjamin Haibe-Kains for assistance with PAM50 analysis and to thank Carla Bullitt, Stuart Tugendreich, Gordon Janaway, and Bryant Macy for assistance with Ingenuity Pathway Analysis. We also like to thank the IUSCC Tissue Procurement and Distribution Core for providing tissues for IHC and qPCR validations. Finally, we would like to thank and acknowledge the TCGA for the sample procurement, production of the TNBC RNA-seq data, and the clinical annotation of TCGA samples used in this publication. This work was supported by the Susan G. Komen for the Cure® (S.E.C., G.W.S., A.V.S., S.B., B.P.S.), Breast Cancer Research Foundation (S.E.C., A.V.S.) and the Catherine Peachey Fund (M.R., S.E.C., G.W.S., A.V.S., C.R., B.P.S.).. M.R. was supported by pre-doctoral fellowships from the National Institutes of Health, NRSA 1T32CA111198 Cancer Biology Training Program and 5TL1RR025759 Indiana Clinical and Translational Sciences Institute Career Development Award.

Conflict of interest

M. Radovich (Speaker honoraria from Life Technologies Corp.), E. E. Hilligoss (employee and stock ownership Life Technologies Corp.), O. Sakarya (former employee Life Technologies Corp; current employee, stock ownership, and funding Genomic Health), F. C. Hyland (Employee and Stock Ownership, Life Technologies Corp), M. Hickenbotham (employee Life Technologies), J. Zhu (former employee Cofactor Genomics, LLC), and J. Glasscock (employee and stock ownership Cofactor Genomics, LLC).

Author information

Authors and Affiliations

  1. Division of General Surgery, Department of Surgery, Indiana University School of Medicine, Indianapolis, IN, USA

    Milan Radovich, Susan E. Clare, Rutuja Atale, Ivanesa Pardo, Bradley A. Hancock, Jeffrey P. Solzak, Heather A. Lillemoe, Rachel J. Blosser, Mi Ran Choi, Candice A. Sauder & Diane Doxey

  2. Division of Hematology/Oncology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA

    Nawal Kassem, Anna Maria V. Storniolo, Mircea Ivan & Bryan P. Schneider

  3. Susan G. Komen for the Cure Tissue Bank, Indianapolis, IN, USA

    Theresa Mathieson, Anna Maria V. Storniolo, Connie Rufenbarger & Jill E. Henry

  4. Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, USA

    Sunil Badve

  5. Department of Medical & Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA

    Yunlong Liu & Bryan P. Schneider

  6. Life Technologies Corporation, South San Francisco, CA, USA

    Eric E. Hilligoss, Onur Sakarya, Fiona C. Hyland & Matthew Hickenbotham

  7. Cofactor Genomics, LLC, St. Louis, MO, USA

    Jin Zhu & Jarret Glasscock

  8. Division of Oncology, Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA

    George W. Sledge

Authors
  1. Milan Radovich
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Susan E. Clare
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Rutuja Atale
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ivanesa Pardo
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Bradley A. Hancock
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jeffrey P. Solzak
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Nawal Kassem
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Theresa Mathieson
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Anna Maria V. Storniolo
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Connie Rufenbarger
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Heather A. Lillemoe
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Rachel J. Blosser
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Mi Ran Choi
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Candice A. Sauder
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Diane Doxey
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Jill E. Henry
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Eric E. Hilligoss
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Onur Sakarya
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. Fiona C. Hyland
    View author publications

    You can also search for this author in PubMed Google Scholar

  20. Matthew Hickenbotham
    View author publications

    You can also search for this author in PubMed Google Scholar

  21. Jin Zhu
    View author publications

    You can also search for this author in PubMed Google Scholar

  22. Jarret Glasscock
    View author publications

    You can also search for this author in PubMed Google Scholar

  23. Sunil Badve
    View author publications

    You can also search for this author in PubMed Google Scholar

  24. Mircea Ivan
    View author publications

    You can also search for this author in PubMed Google Scholar

  25. Yunlong Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  26. George W. Sledge
    View author publications

    You can also search for this author in PubMed Google Scholar

  27. Bryan P. Schneider
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Milan Radovich.

Electronic supplementary material

Rights and permissions

Reprints and permissions

About this article

Cite this article

Radovich, M., Clare, S.E., Atale, R. et al. Characterizing the heterogeneity of triple-negative breast cancers using microdissected normal ductal epithelium and RNA-sequencing. Breast Cancer Res Treat 143, 57–68 (2014). https://doi.org/10.1007/s10549-013-2780-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10549-013-2780-y

Keywords

Search

Navigation