American Association for Cancer Research
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Supplemental Material and Methods from PKCα Attenuates Jagged-1–Mediated Notch Signaling in ErbB-2–Positive Breast Cancer to Reverse Trastuzumab Resistance

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journal contribution
posted on 2023-03-31, 19:08 authored by Kinnari Pandya, Debra Wyatt, Brian Gallagher, Deep Shah, Andrew Baker, Jeffrey Bloodworth, Andrei Zlobin, Antonio Pannuti, Andrew Green, Ian O. Ellis, Aleksandra Filipovic, Jason Sagert, Ajay Rana, Kathy S. Albain, Lucio Miele, Mitchell F. Denning, Clodia Osipo

Materials and Methods



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. Clin Cancer Res; 22(1); 175–86. ©2015 AACR.

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