TY - JOUR
T1 - Caveolin-1 mediates cellular distribution of HER2 and affects trastuzumab binding and therapeutic efficacy
AU - Pereira, Patrícia M.R.
AU - Sharma, Sai Kiran
AU - Carter, Lukas M.
AU - Edwards, Kimberly J.
AU - Pourat, Jacob
AU - Ragupathi, Ashwin
AU - Janjigian, Yelena Y.
AU - Durack, Jeremy C.
AU - Lewis, Jason S.
N1 - Funding Information:
We acknowledge the MSKCC Small-Animal Imaging Core Facility, the Radiochemistry and Molecular Imaging Probe Core, the Anti-tumor Assessment Core and Molecular Cytology Core Facility and the Immune Monitoring Facility, which were supported by NIH grant P30 CA08748. This study was supported in part by the Geoffrey Beene Cancer Research Center of MSKCC. We gratefully acknowledge Mr. William H. and Mrs. Alice Goodwin and the Commonwealth Foundation for Cancer Research and The Center for Experimental Therapeutics of Memorial Sloan Kettering Cancer Center. We thank Dr. Maurizio Scaltriti for reading the manuscript and providing insightful comments. We would also like to acknowledge Ricardo D’Oliveira Albanus from Department of Computational Medicine & Bioinformatics, University of Michigan for assistance in statistical analysis of the data. L.M.C. acknowledges support from the Ruth L. Kirschstein National Research Service Award postdoctoral fellowship (NIH F32-EB025050). P.M.R.P. and S.K.S. gratefully acknowledge the Tow Foundation Postdoctoral Fellowships from the MSKCC Center for Molecular Imaging and Nanotechnology.
Publisher Copyright:
© 2018, The Author(s).
PY - 2018/12/1
Y1 - 2018/12/1
N2 - Human epidermal growth factor receptor 2 (HER2) gene amplification and/or protein overexpression in tumors is a prerequisite for initiation of trastuzumab therapy. Although HER2 is a cell membrane receptor, differential rates of endocytosis and recycling engender a dynamic surface pool of HER2. Since trastuzumab must bind to the extracellular domain of HER2, a depressed HER2 surface pool hinders binding. Using in vivo biological models and cultures of fresh human tumors, we find that the caveolin-1 (CAV1) protein is involved in HER2 cell membrane dynamics within the context of receptor endocytosis. The translational significance of this finding is highlighted by our observation that temporal CAV1 depletion with lovastatin increases HER2 half-life and availability at the cell membrane resulting in improved trastuzumab binding and therapy against HER2-positive tumors. These data show the important role that CAV1 plays in the effectiveness of trastuzumab to target HER2-positive tumors.
AB - Human epidermal growth factor receptor 2 (HER2) gene amplification and/or protein overexpression in tumors is a prerequisite for initiation of trastuzumab therapy. Although HER2 is a cell membrane receptor, differential rates of endocytosis and recycling engender a dynamic surface pool of HER2. Since trastuzumab must bind to the extracellular domain of HER2, a depressed HER2 surface pool hinders binding. Using in vivo biological models and cultures of fresh human tumors, we find that the caveolin-1 (CAV1) protein is involved in HER2 cell membrane dynamics within the context of receptor endocytosis. The translational significance of this finding is highlighted by our observation that temporal CAV1 depletion with lovastatin increases HER2 half-life and availability at the cell membrane resulting in improved trastuzumab binding and therapy against HER2-positive tumors. These data show the important role that CAV1 plays in the effectiveness of trastuzumab to target HER2-positive tumors.
UR - http://www.scopus.com/inward/record.url?scp=85057587316&partnerID=8YFLogxK
U2 - 10.1038/s41467-018-07608-w
DO - 10.1038/s41467-018-07608-w
M3 - Article
C2 - 30510281
AN - SCOPUS:85057587316
SN - 2041-1723
VL - 9
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 5137
ER -