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Keywords {🔍}

cells, trastuzumab, breast, cancer, evs, proteins, patients, article, cell, fig, pubmed, patient, protein, emitted, perp, data, levels, study, response, extracellular, google, scholar, blood, cas, analysis, studies, culture, gnas, rab, erbbpositive, tumor, vesicles, trastuzumabbased, metastatic, gna, bttr, western, biomarkers, treatment, size, itb, upregulated, derived, shown, human, upregulation, therapies, sensitivity, tumors, drug,

Topics {✒️}

low-molecular-weight protein enrichment erbb2-positive breast tumors erbb2-driven breast cancer guanine nucleotide-binding protein trastuzumab-sensitive mcf7/her2-18 her2-enriched extracellular vesicles erbb2-positive cancer formvar/carbon-coated grid undergoing trastuzumab-based therapies t-dm1 binds erbb2 anti-erbb2 antibody trastuzumab quantitative n-linked glycoproteomics research ethics board beta4 integrin-dependent formation metastatic breast cancer median progression-free survival ms/ms spectra assigned mass spectrometric characterization article download pdf 29 mg/ml l-glutamine double-stranded dna capable g-protein-coupled receptors label-free protein quantification accidental time-dependent fluctuations trastuzumab-induced perp upregulation ras-related protein rab-10 trastuzumab-resistant hcc-1419 label-free tic quantification human protein database ras-induced resistance mcf7/her2-18 cells pro-apoptotic protein perp tumor cell-emitted evs breast cancer cells breast cancer res invasive breast carcinoma erbb2-driven downregulation trastuzumab-based treatment regimens erbb2-dependent downregulation failed trastuzumab-based treatments mixed blastic/lytic bone extracellular vesicle formation clin breast cancer breast epithelial cells breast cancer patients detected trastuzumab-dependent upregulation erbb2 drives bc breast cancer metastases cancer cell survival trastuzumab-based therapies shown

Questions {❓}

• How could patients benefit from the use of such biomarkers?
• In the case of patient 9, an apparent increase in the GNAS2 level on day 21 likely reflects artifacts (“image artifacts?

Schema {🗺️}

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         headline:Trastuzumab-induced upregulation of a protein set in extracellular vesicles emitted by ErbB2-positive breast cancer cells correlates with their trastuzumab sensitivity
         description:ErbB2/HER2 oncoprotein often drives breast cancers (BCs) which are treated with the anti-ErbB2 antibody trastuzumab. The efficacy of trastuzumab-based metastatic BC therapies is routinely assessed by imaging studies. Trastuzumab typically becomes ineffective in the case of this disease and is then replaced by other drugs. Biomarkers of BC trastuzumab response could allow imaging studies and the switch to other drugs to occur earlier than is now possible. Moreover, bone-only BC metastases can be hard to measure, and biomarkers of their trastuzumab response could facilitate further treatment decisions. Such biomarkers are presently unavailable. In this study, we searched for proteins whose levels in BC cell-emitted extracellular vesicles (EVs) potentially correlate with BC trastuzumab sensitivity. We isolated EVs from cultured trastuzumab-sensitive and trastuzumab-resistant human BC cells before and after trastuzumab treatment and characterized these EVs by nanoparticle tracking analysis and electron microscopy. We found previously that ErbB2 drives BC by downregulating a pro-apoptotic protein PERP. We now tested whether trastuzumab-induced PERP upregulation in EVs emitted by cultured human BC cells correlates with their trastuzumab sensitivity. We also used mass spectrometry to search for additional proteins whose levels in such EVs reflect BC cell trastuzumab sensitivity. Once we identified proteins whose EV levels correlate with this sensitivity in culture, we explored the feasibility of testing whether their levels in the blood EVs of trastuzumab-treated metastatic BC patients correlate with patients’ response to trastuzumab-based treatments. We found that neither trastuzumab nor acquisition of trastuzumab resistance by BC cells affects the size or morphology of EVs emitted by cultured BC cells. We established that EV levels of proteins PERP, GNAS2, GNA13, ITB1, and RAB10 correlate with BC cell trastuzumab response. Moreover, these proteins were upregulated during trastuzumab-based therapies in the blood EVs of a pilot cohort of metastatic BC patients that benefited from these therapies but not in those derived from patients that failed such treatments. Upregulation of a protein set in EVs derived from cultured breast tumor cells correlates with tumor cell trastuzumab sensitivity. It is feasible to further evaluate these proteins as biomarkers of metastatic BC trastuzumab response.
         datePublished:2020-10-06T00:00:00Z
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            ErbB2
            HER2
            Trastuzumab
            Extracellular vesicles
            Biomarkers
            Cancer Research
            Oncology
            Surgical Oncology
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      headline:Trastuzumab-induced upregulation of a protein set in extracellular vesicles emitted by ErbB2-positive breast cancer cells correlates with their trastuzumab sensitivity
      description:ErbB2/HER2 oncoprotein often drives breast cancers (BCs) which are treated with the anti-ErbB2 antibody trastuzumab. The efficacy of trastuzumab-based metastatic BC therapies is routinely assessed by imaging studies. Trastuzumab typically becomes ineffective in the case of this disease and is then replaced by other drugs. Biomarkers of BC trastuzumab response could allow imaging studies and the switch to other drugs to occur earlier than is now possible. Moreover, bone-only BC metastases can be hard to measure, and biomarkers of their trastuzumab response could facilitate further treatment decisions. Such biomarkers are presently unavailable. In this study, we searched for proteins whose levels in BC cell-emitted extracellular vesicles (EVs) potentially correlate with BC trastuzumab sensitivity. We isolated EVs from cultured trastuzumab-sensitive and trastuzumab-resistant human BC cells before and after trastuzumab treatment and characterized these EVs by nanoparticle tracking analysis and electron microscopy. We found previously that ErbB2 drives BC by downregulating a pro-apoptotic protein PERP. We now tested whether trastuzumab-induced PERP upregulation in EVs emitted by cultured human BC cells correlates with their trastuzumab sensitivity. We also used mass spectrometry to search for additional proteins whose levels in such EVs reflect BC cell trastuzumab sensitivity. Once we identified proteins whose EV levels correlate with this sensitivity in culture, we explored the feasibility of testing whether their levels in the blood EVs of trastuzumab-treated metastatic BC patients correlate with patients’ response to trastuzumab-based treatments. We found that neither trastuzumab nor acquisition of trastuzumab resistance by BC cells affects the size or morphology of EVs emitted by cultured BC cells. We established that EV levels of proteins PERP, GNAS2, GNA13, ITB1, and RAB10 correlate with BC cell trastuzumab response. Moreover, these proteins were upregulated during trastuzumab-based therapies in the blood EVs of a pilot cohort of metastatic BC patients that benefited from these therapies but not in those derived from patients that failed such treatments. Upregulation of a protein set in EVs derived from cultured breast tumor cells correlates with tumor cell trastuzumab sensitivity. It is feasible to further evaluate these proteins as biomarkers of metastatic BC trastuzumab response.
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      dateModified:2020-10-22T00:00:00Z
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         Breast cancer
         ErbB2
         HER2
         Trastuzumab
         Extracellular vesicles
         Biomarkers
         Cancer Research
         Oncology
         Surgical Oncology
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      name:Departments of Pediatrics & Biochemistry and Molecular Biology, Dalhousie University, Halifax, Canada
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