PKCalpha Attenuates Jagged-1-Mediated Notch Signaling in ErbB-2-Positive Breast Cancer to Reverse Trastuzumab Resistance Journal Article


Authors: Pandya, K; Wyatt, D; Gallagher, B.; Shah, D; Baker, A; Bloodworth, J.; Zlobin, A.; Pannuti, A.; Green, A; Ellis, I. O.; Filipovic, A; Sagert, J.; Rana, A.; Albain, K. S.; Miele, L; Denning, M. F.; Osipo, C
Article Title: PKCalpha Attenuates Jagged-1-Mediated Notch Signaling in ErbB-2-Positive Breast Cancer to Reverse Trastuzumab Resistance
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 PKCalpha 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 PKCalpha 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 PKCalpha expression could be the best candidates for anti-Notch therapy. Clin Cancer Res; 1-12. (c)2015 AACR.
Keywords: Hematology and Oncology
Journal Title: Clinical cancer research : an official journal of the American Association for Cancer Research
ISSN: 1078-0432; 1078-0432
Publisher: American Association for Cancer Research  
Date Published: 2015
Language: ENG
DOI/URL:
Notes: LR: 20151026; CI: (c)2015; JID: 9502500; 2015/01/26 [received]; 2015/08/25 [accepted]; 2015/09/08 [aheadofprint]; aheadofprint