The mechanisms of pro-survival action of NRG1 in brain metastatic HER2+ breast cancer cells

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dc.contributor.authorIppolitov, Danyyl
dc.contributor.examiningcommitteeSinha, Namita (Pathology)en_US
dc.contributor.examiningcommitteeKung, Sam (Immunology)en_US
dc.contributor.examiningcommitteeGhavami, Saeid (Human Anatomy and Cell Science)en_US
dc.contributor.supervisorHombach-Klonisch, Sabine
dc.contributor.supervisorKlonisch, Thomas
dc.date.accessioned2023-01-04T20:25:25Z
dc.date.available2023-01-04T20:25:25Z
dc.date.copyright2022-12-22
dc.date.issued2022-12-22
dc.date.submitted2022-12-22T17:15:05Zen_US
dc.degree.disciplineHuman Anatomy and Cell Scienceen_US
dc.degree.levelMaster of Science (M.Sc.)en_US
dc.description.abstractIntroduction: HER2+ (ErbB2+) breast cancer (BC) patients demonstrate a high incidence (30%) of brain metastases (BM). Regardless of the effectiveness of ErbB2 targeting therapies in the therapy of primary HER2+ BC, BM remains a fatal complication. Restricted drug permeability across the blood-brain barrier and specific tumor- and/or brain tumor microenvironment (TME)-derived factors determine the low effectiveness of ErbB targeted drugs in the brain. Neuregulin-1 (NRG-1) is a member of the EGF family which is commonly expressed by cells in the brain TME. NRG1 can bind to ErbB3 and/or ErbB4 receptors and potentially promote activation of alternative signaling pathways under ErbB2 inhibition. Results: The newly established patient-derived HER2+ BC model (BCBM94) that metastasizes to the brain in mice forms well-circumscribed proliferative tumors that are vascularized and surrounded by activated astrocytes. BCBM94 cells are sensitive to the pro-apoptotic actions of the reversible EGFR/ErbB2 small molecule tyrosine kinase inhibitor Lapatinib. NRG1 mitigated cytotoxicity induced by Lapatinib, as shown by higher viability in WST-1 assays and the preserved ability for long-term cell propagation in clonogenicity assays. NRG-1 blocked Lapatinib-driven PARP cleavage and activation of the pro-apoptotic caspases-3/7 and caspase-9. NRG-1 also prevented Lapatinib-induced mitochondrial damage. rhNRG1 rescued phosphorylation of kinase-impaired ErbB3 under combined Lapatinib/rhNRG1 treatment suggesting the involvement of ErbB3 in maintaining the viability of BCBM94 under Lapatinib. The essential role of ErbB3 in the apoptosis inhibiting action of rhNRG1 was confirmed by siRNA-mediated silencing (KD) of the receptor. Upon ErbB3 knockdown, rhNRG1 was no longer able to attenuate the Lapatinib-mediated apoptosis in BCBM94 and this coincided with the mitigated rescue of Survivin and XIAP expression and BAD phosphorylation in BCBM94. These rhNRG1-mediated anti-apoptotic actions were also prevented with exposure to the multi-targeted PI3K-Akt and mTORC1/C2 inhibitor (PI-103) confirming the role of the ErbB3-Akt-mTOR signaling axis in the cell viability rescue. Conclusion: The findings identify BCBM94 as a valuable brain metastasis cell model to study resistance mechanisms under ErbB2 inhibition and demonstrate an important role of NRG1 as a powerful brain TME-derived anti-apoptotic factor that can facilitate resistance of BC brain metastases to ErbB2 targeting therapies.en_US
dc.description.noteFebruary 2023en_US
dc.description.sponsorship- The Cancer Research Society (CRS); Title: “The unfolded protein response (UPR) in early brain metastasis”; CRS PIN: 23303 - The University of Manitoba Collaborative Research Fund (UCRP) - The Rady Faculty of Health Sciences (RFHS) studentshipen_US
dc.identifier.urihttp://hdl.handle.net/1993/37048
dc.language.isoengen_US
dc.rightsopen accessen_US
dc.subjectbreasten_US
dc.subjectcanceren_US
dc.subjectbrainen_US
dc.subjectmetastasisen_US
dc.subjectneuregulinsen_US
dc.subjectErbBen_US
dc.subjectLapatiniben_US
dc.subjectapoptosisen_US
dc.subjectBcl2en_US
dc.subjectmitochondriaen_US
dc.subjectIAPen_US
dc.subjectHER2en_US
dc.titleThe mechanisms of pro-survival action of NRG1 in brain metastatic HER2+ breast cancer cellsen_US
dc.typemaster thesisen_US
local.subject.manitobanoen_US
oaire.awardNumberCRP-159391en_US
oaire.awardTitleThe unfolded protein response (UPR) in early brain metastasisen_US
oaire.awardURIhttps://webapps.cihr-irsc.gc.ca/funding/detail_e?pResearchId=9798810&p_version=CIHR&p_language=E&p_session_id=4347766en_US
project.funder.identifierhttps://doi.org/10.13039/501100000024en_US
project.funder.nameCanadian Institutes of Health Researchen_US
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