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A novel patient-derived xenograft model for claudin-low triple-negative breast cancer

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Abstract

Background

Triple-negative breast cancer (TNBC) subtypes are clinically aggressive and cannot be treated with targeted therapeutics commonly used in other breast cancer subtypes. The claudin-low (CL) molecular subtype of TNBC has high rates of metastases, chemoresistance and recurrence. There exists an urgent need to identify novel therapeutic targets in TNBC; however, existing models utilized in target discovery research are limited. Patient-derived xenograft (PDX) models have emerged as superior models for target discovery experiments because they recapitulate features of patient tumors that are limited by cell-line derived xenograft methods.

Methods

We utilize immunohistochemistry, qRT-PCR and Western Blot to visualize tumor architecture, cellular composition, genomic and protein expressions of a new CL-TNBC PDX model (TU-BcX-2O0). We utilize tissue decellularization techniques to examine extracellular matrix composition of TU-BcX-2O0.

Results

Our laboratory successfully established a TNBC PDX tumor, TU-BCX-2O0, which represents a CL-TNBC subtype and maintains this phenotype throughout subsequent passaging. We dissected TU-BCx-2O0 to examine aspects of this complex tumor that can be targeted by developing therapeutics, including the whole and intact breast tumor, specific cell populations within the tumor, and the extracellular matrix.

Conclusions

Here, we characterize a claudin-low TNBC patient-derived xenograft model that can be utilized for therapeutic research studies.

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References

  1. Alteri R, Bertaut T, Brinton LA, Fedewa S, Freedman RA, Gansler T et al (2015) Breast cancer facts and figures 2015–2016. American Cancer Society Inc, Atlanta

    Google Scholar 

  2. Blows FM, Driver KE, Schmidt MK, Broeks A, van Leeuwen FE, Wesseling J (2010) Subtyping of breast cancer by immunohistochemistry to investigate a relationship between subtype and short and long term survival: a collaborative analysis of data for 10,159 cases from 12 studies. PLOS Med. https://doi.org/10.1371/journal.pmed.1000279

    PubMed  PubMed Central  Google Scholar 

  3. Crown J, O’Shaughnessy J, Gullo G (2012) Emerging targeted therapies in triple-negative breast cancer. Ann Oncol 23(S6):vi56–vi65

    PubMed  Google Scholar 

  4. Stevens KN, Vachon CM, Couch FJ (2013) Genetic susceptibility to triple-negative breast cancer. Cancer Res 73(7):2025–2030

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Engebraaten O, Vollan HKM, Borresen-Dale A-L (2013) Triple-negative breast cancer and the need for new therapeutic targets. Am J Pathol 183(4):1064–1074

    Article  CAS  PubMed  Google Scholar 

  6. Lehmann BD, Jovanovic B, Chen X, Estrada MV, Johnson KN, Shyr Y, Moses HL, Sanders ME, Pietenpol JA (2016) Refinement of triple-negative breast cancer molecular subtypes: implications for neoadjuvant chemotherapy selection. PLoS ONE 11(6):e0157368. https://doi.org/10.1371/journal.pone.0157368

    Article  PubMed  PubMed Central  Google Scholar 

  7. Lehmann BD, Pietenpol JA (2014) Identification and use of biomarkers in treatment strategies for triple-negative breast cancer subtypes. J Pathol 232:142–150

    Article  PubMed  PubMed Central  Google Scholar 

  8. 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 Investig 121(7):2750–2767

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Sabatier R, Finetti P, Guille A, Adelaide J, Chaffanet M, Viens P, Birnbaum D, Bertucci F (2014) Claudin-low breast cancers: clinical, pathological, molecular and prognostic characterization. Mol Cancer 13:228

    Article  PubMed  PubMed Central  Google Scholar 

  10. Pareja F, Geyer FC, Marchio C, Burke KA, Weigelt B, Reis-Filho JS (2016) Triple-negative breast cancer: the importance of molecular and histologic subtyping, and recognition of low-grade variants. NPJ Breast Cancer. https://doi.org/10.1038/npjbcancer.2016.36

    PubMed  PubMed Central  Google Scholar 

  11. Prat A, Parker JS, Karginova O, Fan C, Livasy C, Herschkowitz JI, He X, Perou CM (2010) Phenotypic and molecular characterization of the claudin-low intrinsic subtype of breast cancer. Breast Cancer Res 12(5):R68. https://doi.org/10.1186/bcr2635

    Article  PubMed  PubMed Central  Google Scholar 

  12. Mayer IA, Abramson VG, Lehmann BD, Pientenpol JA (2014) New strategies for triple-negative breast cancer—deciphering the heterogeneity. Clin Cancer Res 20(4):782–790

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Burdall SE, Hanby AM, Lansdown MRJ, Speirs V (2003) Breast cancer cell lines: friend or foe? Breast Cancer Res 5(2):89–95

    Article  PubMed  PubMed Central  Google Scholar 

  14. Cifani P, Kirik U, Waldemarson S, James P (2015) Molecular portrait of breast-cancer-derived cell lines reveals poor similarity with tumors. J Proteome Res 14(7):2819–2827

    Article  CAS  PubMed  Google Scholar 

  15. Manning HC, Buck JR, Cook RS (2016) Mouse models of breast cancer: platforms for discovering precision imaging diagnostics and future cancer medicine. J Nucl Med 57(S1):60S–68S

    Article  PubMed  Google Scholar 

  16. Gillet JP, Clacagno AM, Varma S, Marino M, Green LJ, Vora MI et al (2011) Redefining the relevance of established cancer cell lines to the study of mechanisms of clinical anti-cancer drug resistance. Proc Natl Acad Sci USA 108:18709–18713

    Article  Google Scholar 

  17. Kopetz S, Lemos R, Powis G (2012) The promise of patient-derived xenografts: the best laid plans of mice and men. Clin Cancer Res 18(19):5160–5162

    Article  PubMed  PubMed Central  Google Scholar 

  18. Hidalgo M, Amant F, Biankin AV, Budinska E, Byrne AT, Caldas C et al (2014) Patient-derived xenograft models: an emerging platform for translational cancer research. Cancer Discov 4:998

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Li G (2015) Patient-derived xenograft models for oncology drug discovery. J Cancer Meta Treat 1:8–15

    CAS  Google Scholar 

  20. DeRose YS, Gligorich KM, Wang G, Georgelas A, Bowman P, Courdy SJ, Welm AL, Welm BE (2013) Patient-derived models of human breast cancer: protocols for in vitro and in vivo applications in tumor biology and translational medicine. Curr Protoc Pharmacol 14:14–23

    Google Scholar 

  21. Julien S, Merino-Trigo A, Lacroix L, Pocard M, Goere D, Mariani P et al (2012) Characterization of a large panel of patient-derived tumor xenografts representing the clinical heterogeneity of human colorectal cancer. Clin Cancer Res 18(19):5314–5328

    Article  CAS  PubMed  Google Scholar 

  22. Jin K, Teng L, Shen Y, He K, Xu Z, Li G (2010) Patient-derived human tumor tissue xenografts in immunodeficient mice: a systematic review. Clin Transl Oncol 12:473

    Article  PubMed  Google Scholar 

  23. Tentler JJ, Tan AC, Weekes CD, Jimeno A, Leong S, Pitts TM, Arcaroli JJ, Messersmith WA, Eckhardt SG (2012) Patient-derived xenografts as models for oncology drug development. Nat Rev Clin Oncol 9:338–350

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Whittle JR, Lewis MT, Lindeman GJ, Visvader JE (2015) Patient-derived xenograft models of breast cancer and their predictive power. Breast Cancer Res 17:17

    Article  PubMed  PubMed Central  Google Scholar 

  25. Landis MD, Lehmann BD, Pietenpol JA, Chang JC (2013) Patient-derived breast tumor xenografts facilitating personalized cancer therapy. Breast Cancer Res 15:201

    Article  PubMed  PubMed Central  Google Scholar 

  26. Bertotti A, Migliardi G, Galimi F, Sassi F, Tordi D, Isella C et al (2011) A molecularly annotated platform of patient-derived xenograft (“xenopatients”) identifies HER2 as an effective therapeutic target in cetuximab-resistant colorectal cancer. Cancer Discov 1:508–523

    Article  CAS  PubMed  Google Scholar 

  27. Reyal F, Guyader C, Decraene C, Lucchesi C, Auger N, Assayag F et al (2011) Molecular profiling of patient-derived breast cancer xenografts. Breast Cancer Res 14:R11

    Article  Google Scholar 

  28. Eirew P, Steif A, Khattra J, Ha G, Yap D, Farahani H et al (2013) Dynamics of genomic clones in breast cancer patient xenografts at single-cell resolution. Nature 518:422–426

    Article  Google Scholar 

  29. Rhodes LV, Tate CR, Segar HC, Burks HE, Phamduy TB, Hoang V et al (2014) Suppression of triple-negative breast cancer metastasis by pan-DAC inhibitor panobinostat via inhibition of ZEB family of EMT master regulators. Breast Cancer Res Treat 145(3):593–604

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Pashos NC, Scarritt ME, Eagle ZR, Gimble JM, Chaffin AE, Bunnell BA (2017) Characterization of an acellular scaffold for a tissue engineering approach to the nipple-areolar complex reconstruction. Cells Tissues Org 203:183–193

    Article  CAS  Google Scholar 

  31. Bonvillain RW, Scarritt ME, Pashos NC, Sullivan DE, Betancourt AM, Tsien F et al (2016) Characterization of Rhesus Macaque lung-resident multipotent stromal cells. Cell Gene Ther Insights 2(1):47–92

    Google Scholar 

  32. Al-Khami AA, Zheng L, Del Valle L, Hossain F, Wyczechowska D et al (2017) Exogenous lipid uptake induces metabolic and functional reprogramming of tumor-associated myeloid-derived suppressor cells. OncoImmunology. https://doi.org/10.1080/2162402x.2017.1344804

    PubMed  Google Scholar 

  33. Jézéquel P, Loussouarn D, Charbonnel-Guérin C, Campion L, Vanier A, Gouraud W, Lasla H, Guette C, Valo I, Verriéle V, Campone M (2015) Gene-expression molecular subtyping of triple-negative breast cancer tumors: importance of immune response. Breast Cancer Res 17:43

    Article  PubMed  PubMed Central  Google Scholar 

  34. Lattouf R, Younes R, Lutomski D, Naaman N, Godeau G, Senni K, Changotade S (2014) Picosirius red staining: a useful tool to appraise collagen networks in normal and pathological tissues. J Histochem Cytochem 62(10):751–758

    Article  PubMed  Google Scholar 

  35. Holliday SL, Speirs V (2011) Choosing the right cell line for breast cancer research. Breast Cancer Res 13:215

    Article  PubMed  PubMed Central  Google Scholar 

  36. Chanmee T, Ontong P, Konno K, Itano N (2014) Tumor-associated macrophages as major players in the tumor microenvironment. Cancers (Basel) 6(3):1670–1690

    Article  CAS  Google Scholar 

  37. Yang L, Edwards CM, Mundy GR (2010) Gr-1+CD11b+ Myeloid-derived suppressor cells: formidable partners in tumor metastasis. J Bone Miner Res 25(8):1701–1706

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Gregory AD, Houghton AM (2011) Tumor-associated neutrophils: new targets for cancer therapy. Cancer Res 71(7):2411–2416

    Article  CAS  PubMed  Google Scholar 

  39. Azab B, Bhatt VR, Phookan J, Murukutla S, Kohn N, Terjanian T, Widmann WD (2012) Usefulness of the Neutrophil-to-Lymphocyte ratio in predicting short- and long-term mortality in breast cancer patients. Ann Surg Oncol 19(1):217–224

    Article  PubMed  Google Scholar 

  40. Loch MM, Estrada J, Reske T, Li X, Chen V, Wu X (2013). Triple negative breast cancer in African American women: disparity between women in New Orleans versus Louisiana. Abstract: 2013 ASCO Annual Meeting

  41. Loch MM et al (2016) New Orleans has the highest incidence rates of triple negative breast cancer. Abstract: SABCS 2016

  42. Howlader N, Chen VW, Ries LAG, Loch MM, Lee R, DeSantis C et al (2014) Overview of breast cancer collaborative stage data items—their definitions, quality, usage and clinical implications: a review of SEER data for 2004–2010. Cancer 120(S23):3771–3780

    Article  PubMed  Google Scholar 

  43. Fichtner I, Rolff J, Soong R, Hoffmann J, Hammer S, Sommer A, Becker M, Merk J (2008) Establishment of patient-derived non-small cell lung cancer xenografts as models for the identification of predictive biomarkers. Clin Cancer Res 14(20):6456–6468

    Article  CAS  PubMed  Google Scholar 

  44. Lin D, Wyatt AW, Xue H, Wang Y, Dong X, Haegert A et al (2014) High fidelity patient-derived xenografts for accelerating prostate cancer discovery and drug development. Cancer Res 74(4):1272–1283

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This work was supported by grants from National Institute of Health (NIH) (Grant No. R01-CA125806 (MEB) and R01-CA174785 (BC-B). This work was also supported in part by the Biospecimen Core Laboratory of the Louisiana Cancer Research Consortium. We would especially like to acknowledge Alex Alfortish and Sharon Miller, who played integral roles in coordination and acquisition of TNBC tissue specimen. Additionally, this work was also supported in part by U54 GM104940 from the National Institute of General Medical Sciences of the National Institutes of Health, which funds the Louisiana Clinical and Translational Science Center. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. We are also appreciative of Krewe de Pink for their support in this project. Finally, we would also like to acknowledge the patients who consent to donate their tissue to benefit breast cancer research.

Author information

Authors and Affiliations

  1. Department of Medicine, Section of Hematology & Medical Oncology, Tulane University School of Medicine, New Orleans, LA, USA

    Margarite D. Matossian, Hope E. Burks, Steven Elliott, Van T. Hoang, Bahia M. Wahba, Matthew E. Burow & Bridgette M. Collins-Burow

  2. Tulane Center for Stem Cell Research and Regenerative Medicine, New Orleans, LA, USA

    Annie C. Bowles, Rachel A. Sabol, Nicholas C. Pashos & Bruce A. Bunnell

  3. Department of Biomedical Engineering, Tulane University, New Orleans, LA, USA

    Nicholas C. Pashos, Benjamen O’Donnell & Kristin S. Miller

  4. Department of Pharmacology, Tulane University School of Medicine, New Orleans, LA, USA

    Bruce A. Bunnell & Matthew E. Burow

  5. Department of Pathology, Tulane University School of Medicine, New Orleans, LA, USA

    Krzysztof Moroz

  6. Louisiana Cancer Research Center, Biospecimen Core, New Orleans, LA, USA

    Krzysztof Moroz & Arnold H. Zea

  7. Department of Surgery, Tulane University School of Medicine, New Orleans, LA, USA

    Steven D. Jones

  8. Tulane Cancer Center, Tulane University School of Medicine, New Orleans, LA, USA

    Steven D. Jones & Bridgette M. Collins-Burow

  9. Louisiana State University Health Sciences Center, Biochemistry and Molecular Biology, New Orleans, LA, USA

    Augusto C. Ochoa

  10. Louisiana State University Health Sciences Center, New Orleans, LA, USA

    Arnold H. Zea, Amir A. Al-Khami, Fokhrul Hossain & Lucio Miele

  11. Department of Surgery, Louisiana State University Health Sciences Center, New Orleans, LA, USA

    Adam I. Riker

  12. Department of Biology, Florida Gulf Coast University, Fort Myers, FL, USA

    Lyndsay V. Rhodes

  13. Department of Biological and Agricultural Engineering, Louisiana State University, Baton Rouge, LA, USA

    Elizabeth C. Martin

Authors
  1. Margarite D. Matossian
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  2. Hope E. Burks
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  3. Annie C. Bowles
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  4. Steven Elliott
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  5. Van T. Hoang
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  6. Rachel A. Sabol
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  7. Nicholas C. Pashos
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  8. Benjamen O’Donnell
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  9. Kristin S. Miller
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  10. Bahia M. Wahba
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  11. Bruce A. Bunnell
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  12. Krzysztof Moroz
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  13. Arnold H. Zea
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  14. Steven D. Jones
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  15. Augusto C. Ochoa
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  16. Amir A. Al-Khami
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  17. Fokhrul Hossain
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  18. Adam I. Riker
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  19. Lyndsay V. Rhodes
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  20. Elizabeth C. Martin
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  21. Lucio Miele
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  22. Matthew E. Burow
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  23. Bridgette M. Collins-Burow
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Corresponding author

Correspondence to Bridgette M. Collins-Burow.

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Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

Experiments performed in this study comply with current laws in the United States of America. All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. All procedures performed in studies involving animals were in accordance with the ethical standards of the institution or practice at which the studies were conducted.

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Matossian, M.D., Burks, H.E., Bowles, A.C. et al. A novel patient-derived xenograft model for claudin-low triple-negative breast cancer. Breast Cancer Res Treat 169, 381–390 (2018). https://doi.org/10.1007/s10549-018-4685-2

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  • DOI: https://doi.org/10.1007/s10549-018-4685-2

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