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


METHODS
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.
Molecular Biology Program, Louisiana State University, New Orleans, Louisiana.
Kinnari
K
Pandya
Oncology Research Institute, Louisiana State University, New Orleans, Louisiana.
Debra
D
Wyatt
Oncology Research Institute, Louisiana State University, New Orleans, Louisiana.
Brian
B
Gallagher
Department of Molecular Pharmacology and Therapeutics, Louisiana State University, New Orleans, Louisiana.
Deep
D
Shah
Integrated Cell Biology Program, Louisiana State University, New Orleans, Louisiana.
Andrew
A
Baker
Molecular Biology Program, Louisiana State University, New Orleans, Louisiana.
Jeffrey
J
Bloodworth
Oncology Research Institute, Louisiana State University, New Orleans, Louisiana.
Andrei
A
Zlobin
Louisiana State University, New Orleans, Louisiana.
Antonio
A
Pannuti
Department of Histopathology, University of Nottingham and University Hospital NHS Trust, Nottingham, United Kingdom.
Andrew
A
Green
Department of Histopathology, University of Nottingham and University Hospital NHS Trust, Nottingham, United Kingdom.
Ian O
IO
Ellis
Imperial College of London, London, United Kingdom.
Aleksandra
A
Filipovic
CytomX Therapeutics, San Francisco, California.
Jason
J
Sagert
Department of Molecular Pharmacology and Therapeutics, Louisiana State University, New Orleans, Louisiana.
Ajay
A
Rana
Department of Medicine/Hematology and Oncology, Cardinal Bernardin Cancer Center of Loyola University Chicago: Health Sciences Division, Maywood, Illinois.
Kathy S
KS
Albain
Louisiana State University, New Orleans, Louisiana.
Lucio
L
Miele
Oncology Research Institute, Louisiana State University, New Orleans, Louisiana. Department of Pathology, Cardinal Bernardin Cancer Center of Loyola University Chicago: Health Sciences Division, Maywood, Illinois.
Mitchell F
MF
Denning
Oncology Research Institute, Louisiana State University, New Orleans, Louisiana. Department of Pathology, Cardinal Bernardin Cancer Center of Loyola University Chicago: Health Sciences Division, Maywood, Illinois. Department of Microbiology and Immunology, Cardinal Bernardin Cancer Center of Loyola University Chicago: Health Sciences Division, Maywood, Illinois. cosipo@luc.edu.
Clodia
C
Osipo
D000818:Animals; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D002135:Calcium-Binding Proteins / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D000072100:Jagged-1 Protein; D008565:Membrane Proteins / Q000378:metabolism*; D009364:Neoplasm Recurrence, Local; D011379:Prognosis; D011485:Protein Binding; D051571:Protein Kinase C-alpha / Q000378:metabolism*; D021381:Protein Transport; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D051880:Receptors, Notch / Q000378:metabolism*; D000072099:Serrate-Jagged Proteins; D015398:Signal Transduction / Q000187:drug effects*; D000068878:Trastuzumab / Q000494:pharmacology*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D054875:Ubiquitination; D023041:Xenograft Model Antitumor Assays
D002135:Calcium-Binding Proteins; D036341:Intercellular Signaling Peptides and Proteins; D000072100:Jagged-1 Protein; D008565:Membrane Proteins; D051571:Protein Kinase C-alpha; D018719:Erb-b2 Receptor Tyrosine Kinases; D051880:Receptors, Notch; D000072099:Serrate-Jagged Proteins; D000068878:Trastuzumab; D044767:Ubiquitin-Protein Ligases; C000606273:JAG1 protein, human; C513496:MIB1 ligase, human