Andrew Baker
Notch-1-PTEN-ERK1/2 signaling axis promotes HER2+ breast cancer cell proliferation and stem cell survival
Baker, Andrew; Wyatt, Debra; Bocchetta, Maurizio; Li, Jun; Filipovic, Aleksandra; Green, Andrew; Peiffer, Daniel S.; Fuqua, Suzanne; Miele, Lucio; Albain, Kathy S.; Osipo, Clodia
Authors
Debra Wyatt
Maurizio Bocchetta
Jun Li
Aleksandra Filipovic
ANDREW GREEN ANDREW.GREEN@NOTTINGHAM.AC.UK
Associate Professor
Daniel S. Peiffer
Suzanne Fuqua
Lucio Miele
Kathy S. Albain
Clodia Osipo
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.
Citation
Baker, A., Wyatt, D., Bocchetta, M., Li, J., Filipovic, A., Green, A., …Osipo, C. (2018). Notch-1-PTEN-ERK1/2 signaling axis promotes HER2+ breast cancer cell proliferation and stem cell survival. Oncogene, 37(33), 4489-4504. https://doi.org/10.1038/s41388-018-0251-y
Journal Article Type | Article |
---|---|
Acceptance Date | Mar 16, 2018 |
Online Publication Date | May 10, 2018 |
Publication Date | Aug 31, 2018 |
Deposit Date | Oct 12, 2018 |
Publicly Available Date | Nov 11, 2018 |
Journal | Oncogene |
Print ISSN | 0950-9232 |
Electronic ISSN | 1476-5594 |
Publisher | Nature Publishing Group |
Peer Reviewed | Peer Reviewed |
Volume | 37 |
Issue | 33 |
Pages | 4489-4504 |
DOI | https://doi.org/10.1038/s41388-018-0251-y |
Keywords | Genetics; Cancer Research; Molecular Biology |
Public URL | https://nottingham-repository.worktribe.com/output/1163026 |
Publisher URL | https://www.nature.com/articles/s41388-018-0251-y |
Contract Date | Oct 16, 2018 |
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