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

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