Kinnari Pandya
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
Debra Wyatt
Brian Gallagher
Deep Shah
Andrew Baker
Jeffrey Bloodworth
Andrei Zlobin
Antonio Pannuti
ANDREW GREEN ANDREW.GREEN@NOTTINGHAM.AC.UK
Associate Professor
Professor IAN ELLIS IAN.ELLIS@NOTTINGHAM.AC.UK
Professor of Cancer Pathology
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 |
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