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Learn MoreBackground: Despite the fact that loss of E-cadherin is causal to the development and progression of invasive lobular breast cancer (ILC), no targeted therapy is available to treat this major breast cancer subtype. This study is aimed at identifying clinically targetable pathways that are aberrantly active downstream of E-cadherin loss in ILC.; Methods: Reverse-phase protein array (RPPA) analyses were performed in the context of E-cadherin loss using mouse and human breast cancer cells. A combination of mRNA sequencing, conditioned medium growth assays and CRISPR-Cas9 knock-out experiments were performed to identify and validate activation of oncogenic pathways in ILC. Human ILC samples were employed to validate activation by immunohistochemistry on tissue micro-arrays. Finally, we assessed the effect of pathway inhibition using anoikis resistance and anchorage-dependent growth in vitro.; Results: We demonstrate that E-cadherin loss leads to increased activation of FAK and PI3K/AKT signalling. Autocrine activation of growth factor receptor signalling and its downstream PI3K/AKT hub was a direct consequence of E-cadherin loss, independent of activating mutations in either PIK3CA, AKT or PTEN. Analysis of human ILC samples confirmed pathway activity, and pharmacological inhibition of AKT using AZD5363 and MK2206 resulted in robust inhibition of cell growth and survival of ILC cells in anchorage-dependent and independent conditions. Moreover, our results indicate a role for intracellular FAK in the regulation of ILC anoikis resistance.; Conclusion: Our data demonstrate that E-cadherin loss evokes additional 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. SOURCE: Joost Martens Radboud University
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