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

• Published in: Clinical cancer research Vol. 22; no. 1; pp. 175 - 186
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: United States 01.01.2016
• Subjects: Animals; Breast Neoplasms - drug therapy; Breast Neoplasms - metabolism; Breast Neoplasms - mortality; Breast Neoplasms - pathology; Calcium-Binding Proteins - metabolism; Cell Line, Tumor; Cell Proliferation - drug effects; Disease Models, Animal; Drug Resistance, Neoplasm; Female; Humans; Intercellular Signaling Peptides and Proteins - metabolism; Jagged-1 Protein; Membrane Proteins - metabolism; Neoplasm Recurrence, Local; Prognosis; Protein Binding; Protein Kinase C-alpha - metabolism; Protein Transport; Receptor, ErbB-2 - metabolism; Receptors, Notch - metabolism; Serrate-Jagged Proteins; Signal Transduction - drug effects; Trastuzumab - pharmacology; Ubiquitin-Protein Ligases - metabolism; Ubiquitination; Xenograft Model Antitumor Assays
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-15-0179

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