Notch Activation Induces Akt Signaling via an Autocrine Loop to Prevent Apoptosis in Breast Epithelial Cells

Wellcome Trust Centre for Cell Matrix Research, Faculty of Life Sciences, University of Manchester, Manchester, United Kingdom

^* To whom correspondence should be addressed. E-mail: keith.brennan{at}manchester.ac.uk.

	Abstract

The Notch pathway is aberrantly activated in a wide range of cancers, including breast carcinoma, and is required to maintain the transformed phenotype of many of these tumors. Notch signaling contributes to the transformed phenotype, in part, by preventing apoptosis in response to many different stimuli. However, it is unclear how Notch activation can lead to a general suppression of apoptosis. We show here that Notch signaling induced an autocrine signaling loop that activates Akt in breast epithelial cells. This activation of Akt was necessary for Notch-induced protection against apoptosis in the nontransformed breast epithelial cell line MCF10A. Moreover, inhibiting Notch signaling in breast cancer cells induced a decrease in Akt activity and an increase in sensitivity to apoptosis. Finally, the inhibition of ASK1 by Akt was responsible for the protection from apoptosis induced by DNA damage, as it prevented c-Jun NH₂-terminal kinase-mediated phosphorylation and activation of p53. [Cancer Res 2009;69(12):5015–22]

Key Words: Notch signaling, Akt, breast epithelial cells, autocrine secretion loop