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

Oncogene volume 37, pages 4489–4504 (2018)Cite this article

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Abstract

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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Acknowledgements

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.

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Authors and Affiliations

  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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Electronic supplementary material

Supplementary Figure 1. NICD1 Represses PTEN protein Expression

Supplementary Figure 2. Notch1 is Required for Proliferation of Trastuzumab Resistant Cells

Supplementary Figure 3. Growth Effects of distinct PTEN and Notch1 siRNAs

Supplementary Figure 4. Notch-1-mediated inhibition of PTEN has little effect on AKT phosphorylation

Supplementary Figure 5.Trastuzumab Resistant BT474 Cells Form Larger and More Mammospheres than Sensitive Cells

Supplementary Figure 6. Cancer Stem Cell Survival

Supplementary Table 1. ELDA Results

Supplementary Figure 7. Kaplan–Meier Survival Outcome Based on Notch-1 protein localization and expression

41388_2018_251_MOESM9_ESM.pptx

Supplementary Table 2. Outcome results from Notch-1 protein expression scores in 157-159 cases of HER2+ breast tumor tissue arrays from the Nottingham cohort

41388_2018_251_MOESM10_ESM.pptx

Supplementary Figure 8. Kaplan–Meier Survival Outcome Based on Notch-1 membrane-Intracellular and PTEN Protein Expression

Supplementary Figure 9. Kaplan–Meier Survival Outcome Based on Notch-1 membrane and PTEN Protein Expression

Supplementary Figure 10. Kaplan–Meier Survival Outcome Based on Notch-1 Nuclear and PTEN Protein Expression

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Baker, A., Wyatt, D., Bocchetta, M. et al. Notch-1-PTEN-ERK1/2 signaling axis promotes HER2+ breast cancer cell proliferation and stem cell survival. Oncogene 37, 4489–4504 (2018). https://doi.org/10.1038/s41388-018-0251-y

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