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Inhibition of her2 increases jagged1-dependent breast cancer stem cells: Role for membrane jagged1

Shah, Deep; Wyatt, Debra; Baker, Andrew; Simms, Patricia; Peiffer, Daniel S.; Fernandez, Michelle L.; Rakha, Emad A.; Green, Andrew R.; Filipovic, Aleksandra; Miele, Lucio; Osipo, Clodia

Authors

Deep Shah

Debra Wyatt

Andrew Baker

Patricia Simms

Daniel S. Peiffer

Michelle L. Fernandez

EMAD RAKHA Emad.Rakha@nottingham.ac.uk
Professor of Breast Cancer Pathology

Aleksandra Filipovic

Lucio Miele

Clodia Osipo



Abstract

© 2018 American Association for Cancer Research. Purpose: HER2-positive breast cancer is driven by cells possessing stem-like properties of self-renewal and differentiation, referred to as cancer stem cells (CSC). CSCs are implicated in radiotherapy, chemotherapy resistance, and tumor recurrence. NOTCH promotes breast CSC survival and self-renewal, and overexpression of NOTCH1 and the NOTCH ligand JAGGED1 predict poor outcome. Resistance to anti-HER2 therapy in HER2 þ breast cancer requires NOTCH1, and that combination of trastuzumab and a gamma secretase inhibitor (GSI) prevents tumor relapse in xenograft models. Experimental Design: The current study investigates mechanisms by which HER2 tyrosine kinase activity regulates NOTCH-dependent CSC survival and tumor initiation. Results: Lapatinib-mediated HER2 inhibition shifts the population of HER2 þ breast cancer cells from low membrane JAGGED1 expression to higher levels, independent of sensitivity to anti-HER2 treatment within the bulk cell population. This increase in membrane JAGGED1 is associated with higher NOTCH receptor expression, activation, and enrichment of CSCs in vitro and in vivo. Importantly, lapatinib treatment results in growth arrest and cell death of JAGGED1 low-expressing cells while the JAGGED1 high-expressing cells continue to cycle. High membrane JAGGED1 protein expression predicts poor overall cumulative survival in women with HER2 þ breast cancer. Conclusions: These results indicate that higher membrane JAGGED1 expression may be used to either predict response to anti-HER2 therapy or for detection of NOTCH-sensitive CSCs posttherapy. Sequential blockade of HER2 followed by JAGGED1 or NOTCH could be more effective than simultaneous blockade to prevent drug resistance and tumor progression.

Citation

Shah, D., Wyatt, D., Baker, A., Simms, P., Peiffer, D. S., Fernandez, M. L., …Osipo, C. (2018). Inhibition of her2 increases jagged1-dependent breast cancer stem cells: Role for membrane jagged1. Clinical Cancer Research, 24(18), 4566-4578. https://doi.org/10.1158/1078-0432.CCR-17-1952

Journal Article Type Article
Acceptance Date Jun 4, 2018
Online Publication Date Jun 12, 2018
Publication Date Sep 15, 2018
Deposit Date Jun 18, 2018
Publicly Available Date Mar 28, 2024
Journal Clinical Cancer Research
Print ISSN 1078-0432
Electronic ISSN 1557-3265
Publisher American Association for Cancer Research
Peer Reviewed Peer Reviewed
Volume 24
Issue 18
Pages 4566-4578
DOI https://doi.org/10.1158/1078-0432.CCR-17-1952
Keywords Breast Cancer, HER2, Jagged1, Cancer Stem Cells
Public URL https://nottingham-repository.worktribe.com/output/938235
Publisher URL http://clincancerres.aacrjournals.org/content/24/18/4566