Cancer Immunology, Immunotherapy

, Volume 58, Issue 8, pp 1185–1194

Breast cancer cells expressing stem cell markers CD44+ CD24lo are eliminated by Numb-1 peptide-activated T cells

  • Takashi Mine
  • Satoko Matsueda
  • Yufeng Li
  • Hiroshi Tokumitsu
  • Hui Gao
  • Cristopher Danes
  • Kwong-Kwok Wong
  • Xinhui Wang
  • Soldano Ferrone
  • Constantin G. Ioannides
Original Article


Cancer stem cells (CSC) are resistant to chemo- and radiotherapy. To eliminate cells with phenotypic markers of CSC-like we characterized: (1) expression of CD44, CD24, CD133 and MIC-A/B (NKG2 receptors) in breast (MCF7) and ovarian (SK-OV-3) cells resistant to gemcitabine (GEM), paclitaxel (PTX) and 5-fluorouracil (5-FU) and (2) their elimination by Numb- and Notch-peptide activated CTL. The number of cells in all populations with the luminal CSC phenotype [epithelial specific antigen+ (ESA) CD44hi CD24lo, CD44hi CD133+, and CD133+ CD24lo] increased in drug-resistant MCF7 and SK-OV-3 cells. Similarly, the number of cells with expressed MIC-A/B increased 4 times in drug-resistant tumor cells compared with drug-sensitive cells. GEMRes MCF7 cells had lower levels of the Notch-1-extracellular domain (NECD) and Notch trans-membrane intracellular domain (TMIC) than GEMSens MCF7. The levels of Numb, and Numb-L-[P]-Ser265 were similar in GEMRes and GEMSens MCF7 cells. Only the levels of Numb-L (long)-Ser295 decreased slightly. This finding suggests that Notch-1 cleavage to TMIC is inhibited in GEMRes MCF7 cells. PBMC activated by natural immunogenic peptides Notch-1 (2112–2120) and Numb-1 (87–95) eliminated NICDpositive, CD24hi CD24lo MCF7 cells. It is likely that the immunogenic Numb-1 peptide in MCF7 cells originated from Numb, [P]-lated by an unknown kinase, because staurosporine but not wortmannin and MAPK-inhibitors decreased peptide presentation. Numb and Notch are antagonistic proteins which degrade each other to stop and activate cell proliferation, respectively. Their peptides are presented alternatively. Targeting both antagonistic proteins should be useful to prevent metastases in patients whose tumors are resistant to conventional treatments.


Drug resistance Breast/ovarian Cancer stem cell Notch Numb Peptide 

Supplementary material

262_2008_623_MOESM1_ESM.pdf (54 kb)
Supplementary material (PDF 54 kb)


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Copyright information

© Springer-Verlag 2008

Authors and Affiliations

  • Takashi Mine
    • 1
    • 2
    • 9
  • Satoko Matsueda
    • 1
  • Yufeng Li
    • 1
    • 6
  • Hiroshi Tokumitsu
    • 3
  • Hui Gao
    • 4
  • Cristopher Danes
    • 5
  • Kwong-Kwok Wong
    • 1
  • Xinhui Wang
    • 7
  • Soldano Ferrone
    • 7
  • Constantin G. Ioannides
    • 1
    • 8
  1. 1.Department of Gynecologic OncologyThe University of Texas M. D. Anderson Cancer CenterHoustonUSA
  2. 2.Departments of Immunology and SurgeryKurume University School of MedicineKurumeJapan
  3. 3.Department of Cell Signaling, Faculty of MedicineKagawa UniversityKagawaJapan
  4. 4.Department of Molecular PathologyThe University of Texas M. D. Anderson Cancer CenterHoustonUSA
  5. 5.Department of Molecular and Cellular OncologyThe University of Texas M. D. Anderson Cancer CenterHoustonUSA
  6. 6.Department of Melanoma Medical OncologyThe University of Texas M. D. Anderson Cancer CenterHoustonUSA
  7. 7.Departments of Surgery, Immunology and PathologyUniversity of Pittsburgh Cancer InstitutePittsburghUSA
  8. 8.Department of ImmunologyThe University of Texas M. D. Anderson Cancer CenterHoustonUSA
  9. 9.Multidisciplinary Treatment CenterKurume University School of MedicineKurumeJapan

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