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Notch-1-PTEN-ERK1/2 signaling axis promotes HER2+ breast cancer cell proliferation and stem cell survival

Oncogenevolume 37pages44894504 (2018) | Download Citation


Trastuzumab targets the HER2 receptor on breast cancer cells to attenuate HER2-driven tumor growth. However, resistance to trastuzumab-based therapy remains a major clinical problem for women with HER2+ breast cancer. Breast cancer stem cells (BCSCs) are suggested to be responsible for drug resistance and tumor recurrence. Notch signaling has been shown to promote BCSC survival and self-renewal. Trastuzumab-resistant cells have increased Notch-1 expression. Notch signaling drives cell proliferation in vitro and is required for tumor recurrence in vivo. We demonstrate herein a mechanism by which Notch-1 is required for trastuzumab resistance by repressing PTEN expression to contribute to activation of ERK1/2 signaling. Furthermore, Notch-1-mediated inhibition of PTEN is necessary for BCSC survival in vitro and in vivo. Inhibition of MEK1/2-ERK1/2 signaling in trastuzumab-resistant breast cancer cells mimics effects of Notch-1 knockdown on bulk cell proliferation and BCSC survival. These findings suggest that Notch-1 contributes to trastuzumab resistance by repressing PTEN and this may lead to hyperactivation of ERK1/2 signaling. Furthermore, high Notch-1 and low PTEN mRNA expression may predict poorer overall survival in women with breast cancer. Notch-1 protein expression predicts poorer survival in women with HER2+ breast cancer. These results support a potential future clinical trial combining anti-Notch-1 and anti-MEK/ERK therapy for trastuzumab-resistant breast cancer.

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This work was supported by the American Cancer Society (RSG-11-181-01-TBE) awarded to Dr. Clodia Osipo, the Arthur J. Schmitt Fellowship to Dr. Andrew Baker, and in part by the Breast Cancer Research Foundation to Drs. Kathy Albain and Clodia Osipo. We thank Ianina Bognini for assistance during animal studies.

Author information


  1. Integrated Cell Biology Program, Stritch School of Medicine, Loyola University Chicago, Maywood, IL, 60153, USA

    • Andrew Baker
    •  & Daniel S. Peiffer
  2. Oncology Research Institute, Stritch School of Medicine, Loyola University Chicago, Maywood, IL, 60153, USA

    • Debra Wyatt
    • , Maurizio Bocchetta
    •  & Clodia Osipo
  3. Department of Pathology, Stritch School of Medicine, Loyola University Chicago, Maywood, IL, 60153, USA

    • Maurizio Bocchetta
  4. Department of Applied and Computational Mathematics and Statistics, University of Notre Dame, Notre Dame, IN, USA

    • Jun Li
  5. Imperial College of London, Kensington, London, UK

    • Aleksandra Filipovic
  6. University of Nottingham, Nottingham, UK

    • Andrew Green
  7. MD/PhD Program, Stritch School of Medicine, Loyola University Chicago, Maywood, IL, 60153, USA

    • Daniel S. Peiffer
  8. Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, USA

    • Suzanne Fuqua
  9. Department of Genetics and Stanley S. Scott Cancer Center, Louisiana State University New Orleans, New Orleans, LA, USA

    • Lucio Miele
  10. Department of Medicine: Division of Hematology/Oncology, Stritch School of Medicine, Loyola University Chicago, Maywood, IL, 60153, USA

    • Kathy S. Albain
  11. Department of Microbiology and Immunology, Cardinal Bernardin Cancer Center, Stritch School of Medicine, Loyola University Chicago, Maywood, IL, 60153, USA

    • Clodia Osipo


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Correspondence to Clodia Osipo.

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