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Hypoxia Attenuates ...
Hypoxia Attenuates Trastuzumab Uptake and Trastuzumab-Emtansine (T-DM1) Cytotoxicity through Redistribution of Phosphorylated Caveolin-1
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- Chandran, Vineesh Indira (author)
- Lund University,Lunds universitet,Tumörmikromiljö,Sektion I,Institutionen för kliniska vetenskaper, Lund,Medicinska fakulteten,Tumor microenvironment,Section I,Department of Clinical Sciences, Lund,Faculty of Medicine
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- Mansson, Ann Sofie (author)
- Lund University,Lunds universitet,Tumörmikromiljö,Sektion I,Institutionen för kliniska vetenskaper, Lund,Medicinska fakulteten,Tumor microenvironment,Section I,Department of Clinical Sciences, Lund,Faculty of Medicine
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- Barbachowska, Magdalena (author)
- Lund University,Lunds universitet,Urologisk cancerforskning, Malmö,Forskargrupper vid Lunds universitet,Urological cancer, Malmö,Lund University Research Groups
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- Cerezo-Magana, Myriam (author)
- Lund University,Lunds universitet,Tumörmikromiljö,Sektion I,Institutionen för kliniska vetenskaper, Lund,Medicinska fakulteten,LUCC: Lunds universitets cancercentrum,Övriga starka forskningsmiljöer,Tumor microenvironment,Section I,Department of Clinical Sciences, Lund,Faculty of Medicine,LUCC: Lund University Cancer Centre,Other Strong Research Environments
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- Nodin, Bjorn (author)
- Lund University,Lunds universitet,Terapeutisk patologi,Sektion I,Institutionen för kliniska vetenskaper, Lund,Medicinska fakulteten,LUCC: Lunds universitets cancercentrum,Övriga starka forskningsmiljöer,Therapeutic pathology,Section I,Department of Clinical Sciences, Lund,Faculty of Medicine,LUCC: Lund University Cancer Centre,Other Strong Research Environments
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- Joshi, Bharat (author)
- Univ British Columbia, Dept Cellular & Physiol Sci, Inst Life Sci, Vancouver, BC, Canada.,University of British Columbia
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- Koppada, Neelima (author)
- Genentech Inc, BioAnalyt Sci ADT, GRED, San Francisco, CA USA.
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- Saad, Ola M. (author)
- Genentech Inc, BioAnalyt Sci ADT, GRED, San Francisco, CA USA.
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- Gluz, Oleg (author)
- West German Study Grp, Monchengladbach, Germany.,West German Study Group GmbH
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- Isaksson, Karolin (author)
- Lund University,Lunds universitet,Kirurgi, Lund,Sektion V,Institutionen för kliniska vetenskaper, Lund,Medicinska fakulteten,LUCC: Lunds universitets cancercentrum,Övriga starka forskningsmiljöer,Surgery (Lund),Section V,Department of Clinical Sciences, Lund,Faculty of Medicine,LUCC: Lund University Cancer Centre,Other Strong Research Environments
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- Borgquist, Signe (author)
- Lund University,Lunds universitet,Tumörmikromiljö,Sektion I,Institutionen för kliniska vetenskaper, Lund,Medicinska fakulteten,LUCC: Lunds universitets cancercentrum,Övriga starka forskningsmiljöer,Tumor microenvironment,Section I,Department of Clinical Sciences, Lund,Faculty of Medicine,LUCC: Lund University Cancer Centre,Other Strong Research Environments,Aarhus University
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- Jirstrom, Karin (author)
- Lund University,Lunds universitet,Terapeutisk patologi,Sektion I,Institutionen för kliniska vetenskaper, Lund,Medicinska fakulteten,LUCC: Lunds universitets cancercentrum,Övriga starka forskningsmiljöer,Therapeutic pathology,Section I,Department of Clinical Sciences, Lund,Faculty of Medicine,LUCC: Lund University Cancer Centre,Other Strong Research Environments
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- Nabi, Ivan Robert (author)
- Univ British Columbia, Dept Cellular & Physiol Sci, Inst Life Sci, Vancouver, BC, Canada.,University of British Columbia
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- Jernstrom, Helena (author)
- Lund University,Lunds universitet,Tumörmikromiljö,Sektion I,Institutionen för kliniska vetenskaper, Lund,Medicinska fakulteten,LUCC: Lunds universitets cancercentrum,Övriga starka forskningsmiljöer,Tumor microenvironment,Section I,Department of Clinical Sciences, Lund,Faculty of Medicine,LUCC: Lund University Cancer Centre,Other Strong Research Environments
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- Belting, Mattias (author)
- Uppsala University,Lund University,Lunds universitet,Uppsala universitet,Neuroonkologi,Lund Univ, Dept Clin Sci, Div Oncol & Pathol, Lund, Sweden.;Skane Univ Hosp, Dept Hematol Oncol & Radiophys, Lund, Sweden,Tumörmikromiljö,Sektion I,Institutionen för kliniska vetenskaper, Lund,Medicinska fakulteten,LUCC: Lunds universitets cancercentrum,Övriga starka forskningsmiljöer,Tumor microenvironment,Section I,Department of Clinical Sciences, Lund,Faculty of Medicine,LUCC: Lund University Cancer Centre,Other Strong Research Environments,Skåne University Hospital
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(creator_code:org_t)
- 2020
- 2020
- English.
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In: Molecular Cancer Research. - 1541-7786 .- 1557-3125. ; 18:4, s. 644-656
- Related links:
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http://dx.doi.org/10... (free)
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https://urn.kb.se/re...
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Abstract
Subject headings
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- The antibody-drug conjugate trastuzumab-emtansine (T-DM1) offers an additional treatment option for patients with HER2-amplified tumors. However, primary and acquired resistance is a limiting factor in a significant subset of patients. Hypoxia, a hallmark of cancer, regulates the trafficking of several receptor proteins with potential implications for tumor targeting. Here, we have investigated how hypoxic conditions may regulate T-DM1 treatment efficacy in breast cancer. The therapeutic effect of T-DM1 and its metabolites was evaluated in conjunction with biochemical, flow cytometry, and high-resolution imaging studies to elucidate the functional and mechanistic aspects of hypoxic regulation. HER2 and caveolin-1 expression was investigated in a well-annotated breast cancer cohort. Wefind that hypoxia fosters relative resistance to T-DM1 in HER2(+) cells (SKBR3 and BT474). This effect was not a result of deregulated HER2 expression or resistance to emtansine and its metabolites. Instead, we show that hypoxia-induced translocation of caveolin-1 from cytoplasmic vesicles to the plasma membrane contributes to deficient trastuzumab internalization and T-DM1 chemosensitivity. Caveolin-1 depletion mimicked the hypoxic situation, indicating that vesicular caveolin-1 is indispensable for trastuzumab uptake and T-DM1 cytotoxicity. In vitro studies suggested that HER2 and caveolin-1 are not coregulated, which was supported by IHC analysis in patient tumors. We find that phosphorylation-deficient caveolin-1 inhibits trastuzumab internalization and T-DM1 cytotoxicity, suggesting a specific role for caveolin-1 phosphorylation in HER2 trafficking.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Cancer och onkologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Cancer and Oncology (hsv//eng)
Publication and Content Type
- ref (subject category)
- art (subject category)
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- By the author/editor
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Chandran, Vinees ...
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Mansson, Ann Sof ...
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Barbachowska, Ma ...
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Cerezo-Magana, M ...
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Nodin, Bjorn
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Joshi, Bharat
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show more...
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Koppada, Neelima
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Saad, Ola M.
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Gluz, Oleg
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Isaksson, Karoli ...
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Borgquist, Signe
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Jirstrom, Karin
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Nabi, Ivan Rober ...
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Jernstrom, Helen ...
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Belting, Mattias
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- About the subject
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Clinical Medicin ...
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and Cancer and Oncol ...
- Articles in the publication
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Molecular Cancer ...
- By the university
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Uppsala University
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Lund University