Proteolytic cleavage of amyloid precursor protein by ADAM10 mediates proliferation and migration in breast cancer

Background: Amyloid precursor protein (APP), best known for its association with Alzheimer disease, has recently been implicated in breast cancer progression. However, the precise mechanism involved remains unclear. Here, we investigated the role of APP proteolytic cleavage in breast cancer functions. Methods: The presence of APP proteolytic cleavage products was examined in breast cancer cell lines. The functional roles of APP in breast cancer were studied in vitro and tumor xenograft model using siRNA. The effects of full length APP and the alpha-secretase cleaved ectodomain fragment, soluble APP alpha (sAPP alpha) were further investigated for their overexpression in breast cancers. The alpha-secretase involved was identified. The alpha-secretase expression together with APP was examined in clinical breast cancers. Results: We showed that APP underwent proteolytic cleavage in breast cancer cells to generate sAPP alpha. The sAPP alpha and full length protein mediated breast cancer migration and proliferation, but in different functional extent. This proteolytic cleavage was mediated by ADAM10. Downregulation of APP and ADAM10 brought about similar functional effects. Overexpression of sAPP alpha reversed the effects of ADAM10 downregulation. Interestingly, in patients with non-luminal breast cancers, APP and ADAM10 expression correlated with each other and their co-expression was associated with the worst outcome. Conclusions: These results demonstrated the contributory role of APP cleavage on its oncogenic roles in breast cancer. ADAM10 was the key alpha-secretase. APP and ADAM10 co-expression was associated with worse survival in non-luminal breast cancers. Targeting of APP or its processing by ADAM10 might be a promising treatment option in these cancers. (c) 2018 The Authors. Published by Elsevier B.V.