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Breast Cancer Research and Treatment

, Volume 147, Issue 1, pp 69–80 | Cite as

Vaccination with ErbB-2 peptides prevents cancer stem cell expansion and suppresses the development of spontaneous tumors in MMTV-PyMT transgenic mice

  • Eun-Young Gil
  • Uk-Hyun Jo
  • Hye Jin Lee
  • Jinho Kang
  • Jae Hong Seo
  • Eun Sook Lee
  • Yeul Hong Kim
  • InSun Kim
  • Vy Phan-Lai
  • Mary L. Disis
  • Kyong Hwa ParkEmail author
Preclinical study

Abstract

ErbB-2 has been implicated as a target for cancer-initiating cells in breast and other cancers. ErbB-2-directed peptide vaccines have been shown to be effective in prevention of spontaneous tumorigenesis of breast in neu transgenic mouse model, and cellular immunity is proposed as a mechanism for the anti-tumor efficacy. However, there has been no explanation as to how immunity suppresses tumorigenesis from the early stage carcinogenesis, when ErbB-2 expression in breast is low. Here, we investigated a peptide-based vaccine, which consists of two MHC class II epitopes derived from murine ErbB-2, to prevent the occurrence of spontaneous tumors in breast and assess immune impact on breast cancer stem cells. Female MMTV-PyMT transgenic mice were immunized with either ErbB-2 peptide vaccine, or a peptide from tetanus toxoid, or PBS in immune adjuvant. ErbB-2 peptides vaccine completely suppressed spontaneous breast tumors, and the efficacy was correlated with antigen-specific T-cell and antibody responses. In addition, immune serum from the mice of ErbB-2 vaccine group had an inhibitory effect on mammosphere-forming capacity and signaling through ErbB-2 and downstream Akt pathway in ErbB-2 overexpressing mouse mammary cancer cells. We provide evidence that multi-epitope class II peptides vaccine suppresses tumorigenesis of breast potentially by inhibiting the growth of cancer stem cells. We also suggest that a strategy of inducing strong immune responses using multi-epitope ErbB-2-directed helper vaccine might be useful in preventing breast cancer recurrence.

Keywords

Breast cancer ErbB-2 Peptide vaccine Cancer stem cell Spontaneous tumor 

Notes

Acknowledgments

This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (No. 2009-0068859). MLD is supported by the Athena Distinguished Professor of Breast Cancer Research.

Conflict of interest

The authors declare that they have no conflict of interest.

References

  1. 1.
    Bonnet D, Dick JE (1997) Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nat Med 3(7):730–737CrossRefPubMedGoogle Scholar
  2. 2.
    Glinsky GV (2007) Stem cell origin of death-from-cancer phenotypes of human prostate and breast cancers. Stem Cell Rev 3(1):79–93CrossRefPubMedGoogle Scholar
  3. 3.
    Li C, Heidt DG, Dalerba P, Burant CF, Zhang L, Adsay V, Wicha M, Clarke MF, Simeone DM (2007) Identification of pancreatic cancer stem cells. Cancer Res 67(3):1030–1037. doi: 10.1158/0008-5472.CAN-06-2030 CrossRefPubMedGoogle Scholar
  4. 4.
    Prince ME, Sivanandan R, Kaczorowski A, Wolf GT, Kaplan MJ, Dalerba P, Weissman IL, Clarke MF, Ailles LE (2007) Identification of a subpopulation of cells with cancer stem cell properties in head and neck squamous cell carcinoma. Proc Natl Acad Sci U S A 104(3):973–978. doi: 10.1073/pnas.0610117104 PubMedCentralCrossRefPubMedGoogle Scholar
  5. 5.
    Eramo A, Lotti F, Sette G, Pilozzi E, Biffoni M, Di Virgilio A, Conticello C, Ruco L, Peschle C, De Maria R (2008) Identification and expansion of the tumorigenic lung cancer stem cell population. Cell Death Differ 15(3):504–514. doi: 10.1038/sj.cdd.4402283 CrossRefPubMedGoogle Scholar
  6. 6.
    Slamon DJ, Clark GM, Wong SG, Levin WJ, Ullrich A, McGuire WL (1987) Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science 235(4785):177–182CrossRefPubMedGoogle Scholar
  7. 7.
    Ahmed N, Salsman VS, Kew Y, Shaffer D, Powell S, Zhang YJ, Grossman RG, Heslop HE, Gottschalk S (2010) HER2-specific T cells target primary glioblastoma stem cells and induce regression of autologous experimental tumors. Clin Cancer Res 16(2):474–485. doi: 10.1158/1078-0432.CCR-09-1322 PubMedCentralCrossRefPubMedGoogle Scholar
  8. 8.
    Magnifico A, Albano L, Campaner S, Delia D, Castiglioni F, Gasparini P, Sozzi G, Fontanella E, Menard S, Tagliabue E (2009) Tumor-initiating cells of HER2-positive carcinoma cell lines express the highest oncoprotein levels and are sensitive to trastuzumab. Clin Cancer Res 15(6):2010–2021. doi: 10.1158/1078-0432.CCR-08-1327 CrossRefPubMedGoogle Scholar
  9. 9.
    Paik S, Kim C, Wolmark N (2008) HER2 status and benefit from adjuvant trastuzumab in breast cancer. N Engl J Med 358(13):1409–1411. doi: 10.1056/NEJMc0801440 CrossRefPubMedGoogle Scholar
  10. 10.
    Ithimakin S, Day KC, Malik F, Zen Q, Dawsey SJ, Bersano-Begey TF, Quraishi AA, Ignatoski KW, Daignault S, Davis A, Hall CL, Palanisamy N, Heath AN, Tawakkol N, Luther TK, Clouthier SG, Chadwick WA, Day ML, Kleer CG, Thomas DG, Hayes DF, Korkaya H, Wicha MS (2013) HER2 drives luminal breast cancer stem cells in the absence of HER2 amplification: implications for efficacy of adjuvant trastuzumab. Cancer Res 73(5):1635–1646. doi: 10.1158/0008-5472.CAN-12-3349 PubMedCentralCrossRefPubMedGoogle Scholar
  11. 11.
    Pupa SM, Bufalino R, Invernizzi AM, Andreola S, Rilke F, Lombardi L, Colnaghi MI, Menard S (1996) Macrophage infiltrate and prognosis in c-erbB-2-overexpressing breast carcinomas. J Clin Oncol 14(1):85–94PubMedGoogle Scholar
  12. 12.
    Pupa SM, Tagliabue E, Menard S, Anichini A (2005) HER-2: a biomarker at the crossroads of breast cancer immunotherapy and molecular medicine. J Cell Physiol 205(1):10–18. doi: 10.1002/jcp.20387 CrossRefPubMedGoogle Scholar
  13. 13.
    Disis ML, Calenoff E, McLaughlin G, Murphy AE, Chen W, Groner B, Jeschke M, Lydon N, McGlynn E, Livingston RB et al (1994) Existent T-cell and antibody immunity to HER-2/neu protein in patients with breast cancer. Cancer Res 54(1):16–20PubMedGoogle Scholar
  14. 14.
    Disis ML, Pupa SM, Gralow JR, Dittadi R, Menard S, Cheever MA (1997) High-titer HER-2/neu protein-specific antibody can be detected in patients with early-stage breast cancer. J Clin Oncol 15(11):3363–3367PubMedGoogle Scholar
  15. 15.
    Pupa SM, Menard S, Andreola S, Colnaghi MI (1993) Antibody response against the c-erbB-2 oncoprotein in breast carcinoma patients. Cancer Res 53(24):5864–5866PubMedGoogle Scholar
  16. 16.
    Disis ML, Gad E, Herendeen DR, Lai VP, Park KH, Cecil DL, O’Meara MM, Treuting PM, Lubet RA (2013) A multiantigen vaccine targeting neu, IGFBP-2, and IGF-IR prevents tumor progression in mice with preinvasive breast disease. Cancer Prev Res (Phila) 6(12):1273–1282. doi: 10.1158/1940-6207.CAPR-13-0182 CrossRefGoogle Scholar
  17. 17.
    Knutson KL, Lu H, Stone B, Reiman JM, Behrens MD, Prosperi CM, Gad EA, Smorlesi A, Disis ML (2006) Immunoediting of cancers may lead to epithelial to mesenchymal transition. J Immunol 177(3):1526–1533CrossRefPubMedGoogle Scholar
  18. 18.
    Park KH, Gad E, Goodell V, Dang Y, Wild T, Higgins D, Fintak P, Childs J, Dela Rosa C, Disis ML (2008) Insulin-like growth factor-binding protein-2 is a target for the immunomodulation of breast cancer. Cancer Res 68(20):8400–8409. doi: 10.1158/0008-5472.CAN-07-5891 PubMedCentralCrossRefPubMedGoogle Scholar
  19. 19.
    Lin EY, Jones JG, Li P, Zhu L, Whitney KD, Muller WJ, Pollard JW (2003) Progression to malignancy in the polyoma middle T oncoprotein mouse breast cancer model provides a reliable model for human diseases. Am J Pathol 163(5):2113–2126. doi: 10.1016/S0002-9440(10)63568-7 PubMedCentralCrossRefPubMedGoogle Scholar
  20. 20.
    Rovero S, Amici A, Di Carlo E, Bei R, Nanni P, Quaglino E, Porcedda P, Boggio K, Smorlesi A, Lollini PL, Landuzzi L, Colombo MP, Giovarelli M, Musiani P, Forni G (2000) DNA vaccination against rat her-2/Neu p185 more effectively inhibits carcinogenesis than transplantable carcinomas in transgenic BALB/c mice. J Immunol 165(9):5133–5142CrossRefPubMedGoogle Scholar
  21. 21.
    Quaglino E, Iezzi M, Mastini C, Amici A, Pericle F, Di Carlo E, Pupa SM, De Giovanni C, Spadaro M, Curcio C, Lollini PL, Musiani P, Forni G, Cavallo F (2004) Electroporated DNA vaccine clears away multifocal mammary carcinomas in her-2/neu transgenic mice. Cancer Res 64(8):2858–2864CrossRefPubMedGoogle Scholar
  22. 22.
    Nava-Parada P, Forni G, Knutson KL, Pease LR, Celis E (2007) Peptide vaccine given with a Toll-like receptor agonist is effective for the treatment and prevention of spontaneous breast tumors. Cancer Res 67(3):1326–1334. doi: 10.1158/0008-5472.CAN-06-3290 PubMedCentralCrossRefPubMedGoogle Scholar
  23. 23.
    Nanni P, Landuzzi L, Nicoletti G, De Giovanni C, Rossi I, Croci S, Astolfi A, Iezzi M, Di Carlo E, Musiani P, Forni G, Lollini PL (2004) Immunoprevention of mammary carcinoma in HER-2/neu transgenic mice is IFN-gamma and B cell dependent. J Immunol 173(4):2288–2296CrossRefPubMedGoogle Scholar
  24. 24.
    Brown CE, Starr R, Martinez C, Aguilar B, D’Apuzzo M, Todorov I, Shih CC, Badie B, Hudecek M, Riddell SR, Jensen MC (2009) Recognition and killing of brain tumor stem-like initiating cells by CD8 + cytolytic T cells. Cancer Res 69(23):8886–8893. doi: 10.1158/0008-5472.CAN-09-2687 PubMedCentralCrossRefPubMedGoogle Scholar
  25. 25.
    Pellegatta S, Poliani PL, Corno D, Menghi F, Ghielmetti F, Suarez-Merino B, Caldera V, Nava S, Ravanini M, Facchetti F, Bruzzone MG, Finocchiaro G (2006) Neurospheres enriched in cancer stem-like cells are highly effective in eliciting a dendritic cell-mediated immune response against malignant gliomas. Cancer Res 66(21):10247–10252. doi: 10.1158/0008-5472.CAN-06-2048 CrossRefPubMedGoogle Scholar
  26. 26.
    Xu Q, Liu G, Yuan X, Xu M, Wang H, Ji J, Konda B, Black KL, Yu JS (2009) Antigen-specific T-cell response from dendritic cell vaccination using cancer stem-like cell-associated antigens. Stem Cells 27(8):1734–1740. doi: 10.1002/stem.102 CrossRefPubMedGoogle Scholar
  27. 27.
    Disis ML, Wallace DR, Gooley TA, Dang Y, Slota M, Lu H, Coveler AL, Childs JS, Higgins DM, Fintak PA, dela Rosa C, Tietje K, Link J, Waisman J, Salazar LG (2009) Concurrent trastuzumab and HER2/neu-specific vaccination in patients with metastatic breast cancer. J Clin Oncol 27(28):4685–4692. doi: 10.1200/JCO.2008.20.6789 PubMedCentralCrossRefPubMedGoogle Scholar
  28. 28.
    Wang LX, Plautz GE (2012) T cells sensitized with breast tumor progenitor cell vaccine have therapeutic activity against spontaneous HER2/neu tumors. Breast Cancer Res Treat 134(1):61–70. doi: 10.1007/s10549-011-1912-5 PubMedCentralCrossRefPubMedGoogle Scholar
  29. 29.
    Montgomery RB, Makary E, Schiffman K, Goodell V, Disis ML (2005) Endogenous anti-HER2 antibodies block HER2 phosphorylation and signaling through extracellular signal-regulated kinase. Cancer Res 65(2):650–656PubMedGoogle Scholar
  30. 30.
    Wang X, Sun Y, Wong J, Conklin DS (2013) PPARgamma maintains ERBB2-positive breast cancer stem cells. Oncogene 32(49):5512–5521. doi: 10.1038/onc.2013.217 PubMedCentralCrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Eun-Young Gil
    • 1
  • Uk-Hyun Jo
    • 1
  • Hye Jin Lee
    • 1
  • Jinho Kang
    • 1
  • Jae Hong Seo
    • 1
  • Eun Sook Lee
    • 3
  • Yeul Hong Kim
    • 1
  • InSun Kim
    • 2
  • Vy Phan-Lai
    • 4
  • Mary L. Disis
    • 5
  • Kyong Hwa Park
    • 1
    Email author
  1. 1.Division of Oncology/Hematology, Departments of Internal Medicine, Korea University Anam HospitalKorea University College of MedicineSeoulRepublic of Korea
  2. 2.Departments of Pathology, College of MedicineKorea UniversitySeoulRepublic of Korea
  3. 3.Research Institute and HospitalNational Cancer CenterGoyangKorea
  4. 4.Center for Global Mentoring, UCLA-DOE InstituteUniversity of California Los AngelesLos AngelesUSA
  5. 5.Tumor Vaccine GroupUniversity of WashingtonSeattleUSA

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