{"id":{"repo_id":"dcu","oai_identifier":"oai:doras.dcu.ie:637"},"canonical_url":"https://search.dev.ndltd.org/etd/dcu/oai:doras.dcu.ie:637","repository":{"repo_id":"dcu","name":"Dublin City University","base_url":"http://doras.dcu.ie/cgi/oai2"},"display":{"title":"The role of receptor tyrosine kinase signalling in HER-2-positive cells and trastuzumab (Herceptin) resistance in breast cancer","abstract":"HER-2 gene amplification or overexpression occurs in approximately 25 % of breast cancers, and trastuzumab (Tmab) is a monoclonal antibody currently used to treat patients with HER-2-overexpressing breast cancer. Signalling through alternative receptor tyrosine kinases, such as insulin-like growth factor I receptor (IGF-IR), has been implicated in resistance to Tmab. The main aim of this study was to investigate mechanisms of resistance and in particular the role of IGF-IR in resistance to Tmab. Response to Tmab was analysed in a panel of HER-2-positive breast cancer cell lines; no correlation was found between HER-2, IGF-IR, EGFR expression or phosphorylation and response to Tmab. However, both HER-2 and phospho-HER-2 levels were found to correlate positively with phospho-IGF-IR levels (HER-2, p = 0.16; p-HER-2, p = 0.002). Tmab (T)-resistant cells showed reduced response to Tmab compared to parental cells. T-resistant BT474 have significantly elevated HER-2, phospho-HER-2, EGFR and phospho-EGFR levels compared to parental cells, while T-resistant SKBR3 cells have significantly elevated IGF-IR levels compared to parental cells (p = 0.026). Targeting IGF-IR with anti-IGF-IR siRNA or an IGF-IR tyrosine kinase inhibitor (TKI) (NVP-AEW541) inhibited the growth of both parental and T-resistant SKBR3 and BT474 cells. Combined treatment with Tmab and IGF-IR inhibitors also inhibited significantly more proliferation than single agents in T-resistant BT474 cells, and in parental and T-resistant SKBR3 cells. SKBR3 cells were conditioned in lapatinib (a dual HER-2/EGFR TKI), and the conditioned SKBR3-L cells showed significantly reduced response to lapatinib, and to Tmab, compared to parental SKBR3 cells. Phosphoproteomic analysis revealed alterations in the levels of a number of phosphoproteins in lapatinib resistant cells. HER-2 and IGF-IR expression were measured by immunohistochemistry in tissue microarrays (TMAs) of patient breast tumour samples. Membrane IGF-IR staining correlated inversely with HER-2 expression (p = 0.026). In conclusion, these data suggest that increased signalling through alternative RTKs may play a role in acquired resistance to Tmab. The combination of anti-IGF-IR therapies with Tmab may be clinically beneficial for patients with HER-2-positive breast cancer. We have identified a number of phosphoproteins with potential involvement in trastuzumab and/or lapatinib resistance, and further analysis of these targets may lead to novel therapeutic targets in HER-2-resistant breast cancer.","abstract_html":"HER-2 gene amplification or overexpression occurs in approximately 25 % of breast cancers, and trastuzumab (Tmab) is a monoclonal antibody currently used to treat patients with HER-2-overexpressing breast cancer. Signalling through alternative receptor tyrosine kinases, such as insulin-like growth factor I receptor (IGF-IR), has been implicated in resistance to Tmab. The main aim of this study was to investigate mechanisms of resistance and in particular the role of IGF-IR in resistance to Tmab. Response to Tmab was analysed in a panel of HER-2-positive breast cancer cell lines; no correlation was found between HER-2, IGF-IR, EGFR expression or phosphorylation and response to Tmab. However, both HER-2 and phospho-HER-2 levels were found to correlate positively with phospho-IGF-IR levels (HER-2, p = 0.16; p-HER-2, p = 0.002). Tmab (T)-resistant cells showed reduced response to Tmab compared to parental cells. T-resistant BT474 have significantly elevated HER-2, phospho-HER-2, EGFR and phospho-EGFR levels compared to parental cells, while T-resistant SKBR3 cells have significantly elevated IGF-IR levels compared to parental cells (p = 0.026). Targeting IGF-IR with anti-IGF-IR siRNA or an IGF-IR tyrosine kinase inhibitor (TKI) (NVP-AEW541) inhibited the growth of both parental and T-resistant SKBR3 and BT474 cells. Combined treatment with Tmab and IGF-IR inhibitors also inhibited significantly more proliferation than single agents in T-resistant BT474 cells, and in parental and T-resistant SKBR3 cells. SKBR3 cells were conditioned in lapatinib (a dual HER-2/EGFR TKI), and the conditioned SKBR3-L cells showed significantly reduced response to lapatinib, and to Tmab, compared to parental SKBR3 cells. Phosphoproteomic analysis revealed alterations in the levels of a number of phosphoproteins in lapatinib resistant cells. HER-2 and IGF-IR expression were measured by immunohistochemistry in tissue microarrays (TMAs) of patient breast tumour samples. Membrane IGF-IR staining correlated inversely with HER-2 expression (p = 0.026). In conclusion, these data suggest that increased signalling through alternative RTKs may play a role in acquired resistance to Tmab. The combination of anti-IGF-IR therapies with Tmab may be clinically beneficial for patients with HER-2-positive breast cancer. We have identified a number of phosphoproteins with potential involvement in trastuzumab and/or lapatinib resistance, and further analysis of these targets may lead to novel therapeutic targets in HER-2-resistant breast cancer.","abstract_has_math":false,"creators":["Browne, Brigid"],"institution":"Dublin City University","degree_name":"phd","degree_level":"doctoral","degree_discipline":null,"degree_department":null,"school":null,"contributors":[],"advisors":[],"committee_chairs":[],"committee_members":[],"year":2009,"date_issued":"2009-03","date_published":"2009-03","updated_at":"2026-07-24T06:26:19Z","subjects":["Biotechnology","Cell biology","Cancer"],"languages":["en"],"rights":[],"rights_urls":[],"identifier_entries":[]},"links":{"outbound_url":null,"outbound_label":null,"outbound_source":null},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:creator","label":"Author","values":["Browne, Brigid"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date","label":"Dc Date","values":["2009-03"]},{"key":"dc:date.issued","label":"Date","values":["2009-03"]},{"key":"dc:publisher.institution","label":"Dc Publisher Institution","values":["Dublin City University"]},{"key":"dc:relation.isreferencedby","label":"Dc Relation Isreferencedby","values":["https://doras.dcu.ie/637/"]},{"key":"dc:type","label":"Dc Type","values":["Thesis"]},{"key":"dc:type.qualificationlevel","label":"Dc Type Qualificationlevel","values":["doctoral"]},{"key":"dc:type.qualificationname","label":"Dc Type Qualificationname","values":["phd"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["Biotechnology","Cell biology","Cancer"]}]},{"id":"language_rights","label":"Language and Rights","entries":[{"key":"dc:language","label":"Dc Language","values":["en"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier.uri","label":"Identifier URI","values":["https://doras.dcu.ie/637/1/Brigid_Browne_2008.pdf"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description.abstract","label":"Abstract","values":["HER-2 gene amplification or overexpression occurs in approximately 25 % of breast cancers, and trastuzumab (Tmab) is a monoclonal antibody currently used to treat patients with HER-2-overexpressing breast cancer. Signalling through alternative receptor tyrosine kinases, such as insulin-like growth factor I receptor (IGF-IR), has been implicated in resistance to Tmab. The main aim of this study was to investigate mechanisms of resistance and in particular the role of IGF-IR in resistance to Tmab. Response to Tmab was analysed in a panel of HER-2-positive breast cancer cell lines; no correlation was found between HER-2, IGF-IR, EGFR expression or phosphorylation and response to Tmab. However, both HER-2 and phospho-HER-2 levels were found to correlate positively with phospho-IGF-IR levels (HER-2, p = 0.16; p-HER-2, p = 0.002). Tmab (T)-resistant cells showed reduced response to Tmab compared to parental cells. T-resistant BT474 have significantly elevated HER-2, phospho-HER-2, EGFR and phospho-EGFR levels compared to parental cells, while T-resistant SKBR3 cells have significantly elevated IGF-IR levels compared to parental cells (p = 0.026). Targeting IGF-IR with anti-IGF-IR siRNA or an IGF-IR tyrosine kinase inhibitor (TKI) (NVP-AEW541) inhibited the growth of both parental and T-resistant SKBR3 and BT474 cells. Combined treatment with Tmab and IGF-IR inhibitors also inhibited significantly more proliferation than single agents in T-resistant BT474 cells, and in parental and T-resistant SKBR3 cells. SKBR3 cells were conditioned in lapatinib (a dual HER-2/EGFR TKI), and the conditioned SKBR3-L cells showed significantly reduced response to lapatinib, and to Tmab, compared to parental SKBR3 cells. Phosphoproteomic analysis revealed alterations in the levels of a number of phosphoproteins in lapatinib resistant cells. HER-2 and IGF-IR expression were measured by immunohistochemistry in tissue microarrays (TMAs) of patient breast tumour samples. Membrane IGF-IR staining correlated inversely with HER-2 expression (p = 0.026). In conclusion, these data suggest that increased signalling through alternative RTKs may play a role in acquired resistance to Tmab. The combination of anti-IGF-IR therapies with Tmab may be clinically beneficial for patients with HER-2-positive breast cancer. We have identified a number of phosphoproteins with potential involvement in trastuzumab and/or lapatinib resistance, and further analysis of these targets may lead to novel therapeutic targets in HER-2-resistant breast cancer."]},{"key":"dc:format","label":"Dc Format","values":["application/pdf"]},{"key":"dc:title","label":"Title","values":["The role of receptor tyrosine kinase signalling in HER-2-positive cells and trastuzumab (Herceptin) resistance in breast cancer"]}]}],"canonical_facts":{"dc:creator":["Browne, Brigid"],"dc:date":["2009-03"],"dc:date.issued":["2009-03"],"dc:description.abstract":["HER-2 gene amplification or overexpression occurs in approximately 25 % of breast cancers, and trastuzumab (Tmab) is a monoclonal antibody currently used to treat patients with HER-2-overexpressing breast cancer. Signalling through alternative receptor tyrosine kinases, such as insulin-like growth factor I receptor (IGF-IR), has been implicated in resistance to Tmab. The main aim of this study was to investigate mechanisms of resistance and in particular the role of IGF-IR in resistance to Tmab. Response to Tmab was analysed in a panel of HER-2-positive breast cancer cell lines; no correlation was found between HER-2, IGF-IR, EGFR expression or phosphorylation and response to Tmab. However, both HER-2 and phospho-HER-2 levels were found to correlate positively with phospho-IGF-IR levels (HER-2, p = 0.16; p-HER-2, p = 0.002). Tmab (T)-resistant cells showed reduced response to Tmab compared to parental cells. T-resistant BT474 have significantly elevated HER-2, phospho-HER-2, EGFR and phospho-EGFR levels compared to parental cells, while T-resistant SKBR3 cells have significantly elevated IGF-IR levels compared to parental cells (p = 0.026). Targeting IGF-IR with anti-IGF-IR siRNA or an IGF-IR tyrosine kinase inhibitor (TKI) (NVP-AEW541) inhibited the growth of both parental and T-resistant SKBR3 and BT474 cells. Combined treatment with Tmab and IGF-IR inhibitors also inhibited significantly more proliferation than single agents in T-resistant BT474 cells, and in parental and T-resistant SKBR3 cells. SKBR3 cells were conditioned in lapatinib (a dual HER-2/EGFR TKI), and the conditioned SKBR3-L cells showed significantly reduced response to lapatinib, and to Tmab, compared to parental SKBR3 cells. Phosphoproteomic analysis revealed alterations in the levels of a number of phosphoproteins in lapatinib resistant cells. HER-2 and IGF-IR expression were measured by immunohistochemistry in tissue microarrays (TMAs) of patient breast tumour samples. Membrane IGF-IR staining correlated inversely with HER-2 expression (p = 0.026). In conclusion, these data suggest that increased signalling through alternative RTKs may play a role in acquired resistance to Tmab. The combination of anti-IGF-IR therapies with Tmab may be clinically beneficial for patients with HER-2-positive breast cancer. We have identified a number of phosphoproteins with potential involvement in trastuzumab and/or lapatinib resistance, and further analysis of these targets may lead to novel therapeutic targets in HER-2-resistant breast cancer."],"dc:format":["application/pdf"],"dc:identifier.uri":["https://doras.dcu.ie/637/1/Brigid_Browne_2008.pdf"],"dc:language":["en"],"dc:publisher.institution":["Dublin City University"],"dc:relation.isreferencedby":["https://doras.dcu.ie/637/"],"dc:subject":["Biotechnology","Cell biology","Cancer"],"dc:title":["The role of receptor tyrosine kinase signalling in HER-2-positive cells and trastuzumab (Herceptin) resistance in breast cancer"],"dc:type":["Thesis"],"dc:type.qualificationlevel":["doctoral"],"dc:type.qualificationname":["phd"]},"updated_at":"2026-07-24T06:26:19Z"}