2. Academic Validation
  3. E-cadherin loss induces targetable autocrine activation of growth factor signalling in lobular breast cancer

E-cadherin loss induces targetable autocrine activation of growth factor signalling in lobular breast cancer

  • Sci Rep. 2018 Oct 18;8(1):15454. doi: 10.1038/s41598-018-33525-5.
Katy Teo 1,  Laura Gómez-Cuadrado 1,  Milou Tenhagen 2,  Adam Byron 1,  Max Rätze 2,  Miranda van Amersfoort 2,  Jojanneke Renes 2,  Eric Strengman 2,  Amit Mandoli 3,  Abhishek A Singh 3,  Joost H Martens 3,  Hendrik G Stunnenberg 3,  Paul J van Diest 2,  Valerie G Brunton 4,  Patrick W B Derksen 5
Affiliations

Affiliations

  • 1 Cancer Research UK Edinburgh Centre, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom.
  • 2 Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands.
  • 3 Department of Molecular Biology, Faculty of Science, Nijmegen Centre for Molecular Life Sciences, Radboud University, Nijmegen, The Netherlands.
  • 4 Cancer Research UK Edinburgh Centre, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom. [email protected].
  • 5 Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands. [email protected].
PMID: 30337563 DOI: 10.1038/s41598-018-33525-5
Abstract

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.

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