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PKC? attenuates jagged-1-mediated notch signaling in ErbB-2-positive breast cancer to reverse trastuzumab resistance

Pandya, Kinnari; Wyatt, Debra; Gallagher, Brian; Shah, Deep; Baker, Andrew; Bloodworth, Jeffrey; Zlobin, Andrei; Pannuti, Antonio; Green, Andrew; Ellis, Ian O.; Filipovic, Aleksandra; Sagert, Jason; Rana, Ajay; Albain, Kathy S.; Miele, Lucio; Denning, Mitchell F.; Osipo, Clodia

Authors

Kinnari Pandya

Debra Wyatt

Brian Gallagher

Deep Shah

Andrew Baker

Jeffrey Bloodworth

Andrei Zlobin

Antonio Pannuti

Ian O. Ellis

Aleksandra Filipovic

Jason Sagert

Ajay Rana

Kathy S. Albain

Lucio Miele

Mitchell F. Denning

Clodia Osipo



Abstract

Purpose: Breast cancer is the second leading cause of cancer mortality among women worldwide. The major problem with current treatments is tumor resistance, recurrence, and disease progression. ErbB-2–positive breast tumors are aggressive and frequently become resistant to trastuzumab or lapatinib. We showed previously that Notch-1 is required for trastuzumab resistance in ErbB-2–positive breast cancer.

Experimental Design: Here, we sought to elucidate mechanisms by which ErbB-2 attenuates Notch signaling and how this is reversed by trastuzumab or lapatinib.

Results: The current study elucidates a novel Notch inhibitory mechanism by which PKCα downstream of ErbB-2 (i) restricts the availability of Jagged-1 at the cell surface to transactivate Notch, (ii) restricts the critical interaction between Jagged-1 and Mindbomb-1, an E3 ligase that is required for Jagged-1 ubiquitinylation and subsequent Notch activation, (iii) reverses trastuzumab resistance in vivo, and (iv) predicts better outcome in women with ErbB-2–positive breast cancer.

Conclusions: The clinical impact of these studies is PKCα is potentially a good prognostic marker for low Notch activity and increased trastuzumab sensitivity in ErbB-2–positive breast cancer. Moreover, women with ErbB-2–positive breast tumors expressing high Notch activation and low PKCα expression could be the best candidates for anti-Notch therapy.

Journal Article Type Article
Acceptance Date Aug 25, 2015
Online Publication Date Sep 8, 2015
Publication Date 2016-01
Deposit Date Apr 24, 2018
Print ISSN 1078-0432
Publisher American Association for Cancer Research
Peer Reviewed Peer Reviewed
Volume 22
Issue 1
Pages 175-186
DOI https://doi.org/10.1158/1078-0432.CCR-15-0179
Public URL https://nottingham-repository.worktribe.com/output/1118165
Publisher URL http://clincancerres.aacrjournals.org/content/22/1/175
PMID 26350262