RT info:eu-repo/semantics/article
T1 E-cadherin loss induces targetable autocrine activation of growth factor signalling in lobular breast cancer
A1 Teo, Katy
A1 Gómez Cuadrado, Laura
A1 Tenhagen, Milou
A1 Byron, Adam
A1 Ratze, Max
A1 Amersfoort, Miranda van
A1 Renes, Jojanneke
A1 Strengman, Eric
A1 Mandoli, Amit
A1 Singh, Abhishek
A1 Martens, Joost H.A.
A1 Stunnenberg, Hendrik G.
A1 Diest, Paul J. van
A1 Brunton, Valerie G.
A1 Derksen, Patrick W.B.
K1 E-cadherin
K1 Invasive lobular carcinoma
K1 Breast cancer treatment
K1 P13-kinase
K1 AKT
K1 Targeted treatment
K1 Reverse-phase protein array
K1 Oncología
K1 Oncology
K1 Química orgánica
K1 Chemistry, Organic
K1 Salud
K1 Health
AB 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.
PB Nature Research
YR 2018
FD 2018-10
LK http://hdl.handle.net/10259/9797
UL http://hdl.handle.net/10259/9797
LA eng
NO 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).
DS Repositorio Institucional de la Universidad de Burgos
RD 22-dic-2024