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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

Andrew Baker

Debra Wyatt

Maurizio Bocchetta

Jun Li

Aleksandra Filipovic

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.

Journal Article Type Article
Publication Date Aug 31, 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
APA6 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. doi:10.1038/s41388-018-0251-y
DOI https://doi.org/10.1038/s41388-018-0251-y
Keywords Genetics; Cancer Research; Molecular Biology
Publisher URL https://www.nature.com/articles/s41388-018-0251-y

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