@article { , title = {Notch-1-PTEN-ERK1/2 signaling axis promotes HER2+ breast cancer cell proliferation and stem cell survival}, 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.}, doi = {10.1038/s41388-018-0251-y}, eissn = {1476-5594}, issn = {0950-9232}, issue = {33}, journal = {Oncogene}, note = { 6 mo. embargo. OL 16.10.2018}, pages = {4489-4504}, publicationstatus = {Published}, publisher = {Nature Publishing Group}, url = {https://nottingham-repository.worktribe.com/output/1163026}, volume = {37}, keyword = {Nottingham Breast Cancer Research Centre, Genetics, Cancer Research, Molecular Biology}, year = {2018}, author = {Baker, Andrew and Wyatt, Debra and Bocchetta, Maurizio and Li, Jun and Filipovic, Aleksandra and Green, Andrew and Peiffer, Daniel S. and Fuqua, Suzanne and Miele, Lucio and Albain, Kathy S. and Osipo, Clodia} }