2026-04-17T13:51:42Zhttps://riubu.ubu.es/oai/request

oai:riubu.ubu.es:10259/97972024-12-18T01:05:22Zcom_10259_6168com_10259_5086com_10259_2604col_10259_6169

Teo, Katy Gómez Cuadrado, Laura Tenhagen, Milou Byron, Adam Ratze, Max Amersfoort, Miranda van Renes, Jojanneke Strengman, Eric Mandoli, Amit Singh, Abhishek Martens, Joost H.A. Stunnenberg, Hendrik G. Diest, Paul J. van Brunton, Valerie G. Derksen, Patrick W.B. 2024-12-17T12:18:48Z 2024-12-17T12:18:48Z 2018-10 http://hdl.handle.net/10259/9797 10.1038/s41598-018-33525-5 2045-2322 Despite the fact that loss of E-cadherin is causal to the development and progression of invasive lobular carcinoma (ILC), options to treat this major breast cancer subtype are limited if tumours develop resistance to anti- oestrogen treatment regimens. This study aimed to identify clinically targetable pathways that are aberrantly active downstream of E-cadherin loss in ILC. Using a combination of reverse-phase protein array (RPPA) analyses, mRNA sequencing, conditioned medium growth assays and CRISPR/Cas9-based knock-out experiments, we demonstrate that E-cadherin loss causes increased responsiveness to autocrine growth factor receptor (GFR)-dependent activation of phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)/Akt signalling. Autocrine activation of GFR signalling and its downstream PI3K/Akt hub was independent of oncogenic mutations in PIK3CA, AKT1 or PTEN. Analyses of human ILC samples confirmed growth factor production and pathway activity. Pharmacological inhibition of Akt using AZD5363 or MK2206 resulted in robust inhibition of cell growth and survival of ILC cells, and impeded tumour growth in a mouse ILC model. Because E-cadherin loss evokes hypersensitisation of PI3K/Akt activation independent of oncogenic mutations in this pathway, we propose clinical intervention of PI3K/Akt in ILC based on functional E-cadherin inactivation, irrespective of activating pathway mutations. Tis study was fnancially supported by grants from Cancer Research UK (C157/A15703), the Wellcome Trust (101911), the Netherlands Organization for Scientifc Research (NWO/ZonMW-VIDI 0616.096.318), Foundation Vrienden UMC Utrecht (11.081) and the Dutch Cancer Society (KWF-UU-2011–5230 and KWF-UU-10456). application/pdf eng Nature Research Scientific Reports. 2018, V. 8, n. 15454 https://doi.org/10.1038/s41598-018-33525-5 Atribución 4.0 Internacional http://creativecommons.org/licenses/by/4.0/ info:eu-repo/semantics/openAccess E-cadherin Invasive lobular carcinoma Breast cancer treatment P13-kinase AKT Targeted treatment Reverse-phase protein array Oncología Química orgánica Salud Oncology Chemistry, Organic Health E-cadherin loss induces targetable autocrine activation of growth factor signalling in lobular breast cancer info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion Scientific Reports 8 15454