2026-04-22T20:21:33Zhttps://riubu.ubu.es/oai/request

oai:riubu.ubu.es:10259/97912024-12-18T01:05:27Zcom_10259_6168com_10259_5086com_10259_2604col_10259_6169

Creedon, Helen 734d1ce5-7f42-46dc-9279-61e54a069aa5 600 Balderstone, Lucy A. 4bbee948-fc92-4808-8845-d84bf6546230 600 Muir, Morwenna 8b73d7aa-c957-4611-93d4-d0a6a381ab02 600 Balla, Jozef 979949ae-c73f-4cfd-aa09-ec0d318e4f99 600 Gómez Cuadrado, Laura 9514b3a3-cf2c-47f7-8cbe-5a961c5653b5 600 Tracey, Natasha 1adaf98a-6db7-449c-bec5-ac1f354969b0 600 Loane, Joseph d148f9a4-53a9-4f09-941c-6dd49ab35eea 600 Kilnowska, Teresa e54e4f8e-b3f0-44cb-890d-71970067730e 600 Muller, William J. a53a0c85-be45-4a26-bdf9-160c4bd045cf 600 Brunton, Valerie G. 647cce9b-b9ca-4776-9053-5bfb5be6858d 600 2024-12-17T09:09:11Z 2024-12-17T09:09:11Z 2016-02 1754-8403 http://hdl.handle.net/10259/9791 10.1242/dmm.023143 1754-8411 Resistance to human epidermal growth factor receptor 2 (HER2)-targeted therapies presents a major clinical problem. Although preclinical studies have identified a number of possible mechanisms, clinical validation has been difficult. This is most likely to reflect the reliance on cell-line models that do not recapitulate the complexity and heterogeneity seen in human tumours. Here, we show the utility of a genetically engineered mouse model of HER2-driven breast cancer (MMTV-NIC) to define mechanisms of resistance to the pan-HER family inhibitor AZD8931. Genetic manipulation of MMTV-NIC mice demonstrated that loss of phosphatase and tensin homologue (PTEN) conferred de novo resistance to AZD8931, and a tumour fragment transplantation model was established to assess mechanisms of acquired resistance. Using this approach, 50% of tumours developed resistance to AZD8931. Analysis of the resistant tumours showed two distinct patterns of resistance: tumours in which reduced membranous HER2 expression was associated with an epithelial-to-mesenchymal transition (EMT) and resistant tumours that retained HER2 expression and an epithelial morphology. The plasticity of the EMT phenotype was demonstrated upon re-implantation of resistant tumours that then showed a mixed epithelial and mesenchymal phenotype. Further AZD8931 treatment resulted in the generation of secondary resistant tumours that again had either undergone EMT or retained their original epithelial morphology. The data provide a strong rationale for basing therapeutic decisions on the biology of the individual resistant tumour, which can be very different from that of the primary tumour and will be specific to individual patients. This work was supported by Cancer Research UK grants [C157/A15703, C157/A9148 and C6088/A12063] and a Medical Research Council/AstraZeneca Case Award [G0900184-4/1]. application/pdf eng The Company of Biologists Disease Models & Mechanisms. 2016, V. 9, n. 2, p. 131-140 https://doi.org/10.1242/dmm.023143 Attribution 3.0 Unported http://creativecommons.org/licenses/by/3.0/ info:eu-repo/semantics/openAccess HER2 Breast cancer Resistance Epithelial-to-mesenchymal transition Salud Oncología Medicina Health Oncology Medicine Use of a genetically engineered mouse model as a preclinical tool for HER2 breast cancer info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion Disease Models & Mechanisms 9 2 131 140 THUMBNAIL Creedon-dm&m_2016.pdf.jpg Creedon-dm&m_2016.pdf.jpg IM Thumbnail image/jpeg 5213 https://riubu.ubu.es/bitstream/10259/9791/4/Creedon-dm%26m_2016.pdf.jpg 13e60d91e880eff2324aa46b2d2a4a2b MD5 4 LICENSE license.txt license.txt text/plain; charset=utf-8 1362 https://riubu.ubu.es/bitstream/10259/9791/3/license.txt 5d013bfa6e473ff0db22cd82a4d71a70 MD5 3 CC-LICENSE license_rdf license_rdf application/rdf+xml; charset=utf-8 908 https://riubu.ubu.es/bitstream/10259/9791/2/license_rdf f9a6a4096bf314846151c97900b2090d MD5 2 ORIGINAL Creedon-dm&m_2016.pdf Creedon-dm&m_2016.pdf application/pdf 10165062 https://riubu.ubu.es/bitstream/10259/9791/1/Creedon-dm%26m_2016.pdf cecaca40a9b533511b463867fc357147 MD5 1 10259/9791 oai:riubu.ubu.es:10259/9791 2024-12-18 02:05:27.526 Repositorio Institucional de la Universidad de Burgos bubrep@ubu.es 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