2026-04-17T12:07:37Zhttps://riubu.ubu.es/oai/request

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

00925njm 22002777a 4500 dc Teo, Katy author Gómez Cuadrado, Laura author Tenhagen, Milou author Byron, Adam author Ratze, Max author Amersfoort, Miranda van author Renes, Jojanneke author Strengman, Eric author Mandoli, Amit author Singh, Abhishek author Martens, Joost H.A. author Stunnenberg, Hendrik G. author Diest, Paul J. van author Brunton, Valerie G. author Derksen, Patrick W.B. author 2018-10 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. http://hdl.handle.net/10259/9797 10.1038/s41598-018-33525-5 2045-2322 E-cadherin Invasive lobular carcinoma Breast cancer treatment P13-kinase AKT Targeted treatment Reverse-phase protein array E-cadherin loss induces targetable autocrine activation of growth factor signalling in lobular breast cancer