CK1e Is Required for Breast Cancers Dependent on b- Catenin Activity

Background: Aberrant b-catenin signaling plays a key role in several cancer types, notably colon, liver and breast cancer. However approaches to modulate b-catenin activity for therapeutic purposes have proven elusive to date. Methodology: To uncover genetic dependencies in breast cancer cells that harbor active b-catenin signaling, we performed RNAi-based loss-of-function screens in breast cancer cell lines in which we had characterized b-catenin activity. Here we identify CSNK1E, the gene encoding casein kinase 1 epsilon (CK1e) as required specifically for the proliferation of breast cancer cells with activated b-catenin and confirm its role as a positive regulator of b-catenin-driven transcription. Furthermore, we demonstrate that breast cancer cells that harbor activated b-catenin activity exhibit enhanced sensitivity to pharmacological blockade of Wnt/b-catenin signaling. We also find that expression of CK1e is able to promote oncogenic transformation of human cells in a b-catenin-dependent manner. Conclusions/Significance: These studies identify CK1e as a critical contributor to activated b-catenin signaling in cancer and suggest it may provide a potential therapeutic target for cancers that harbor active b-catenin. More generally, these observations delineate an approach that can be used to identify druggable synthetic lethal interactions with signaling pathways that are frequently activated in cancer but are difficult to target with the currently available small molecule inhibitors. Citation: Kim SY, Dunn IF, Firestein R, Gupta P, Wardwell L, et al. (2010) CK1e Is Required for Breast Cancers Dependent on b-Catenin Activity. PLoS ONE 5(2): e8979. doi:10.1371/journal.pone.0008979 Editor: Mikhail V. Blagosklonny, Roswell Park Cancer Institute, United States of America Received October 8, 2009; Accepted January 11, 2010; Published February 1, 2010 Copyright: 2010 Kim et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: This work was supported in part by a Department of Defense postdoctoral fellowship (S.Y.K.), the Brain Science Foundation and Warren-WhitmanRichardson Foundation (I.D.), K08 CA134836-01 from National Institutes of Health (NIH): Mentored Clinical Scientist Award and P50 CA127003: GI SPORE Career Development Grant (R.F.), R33 CA128625 (W.C.H.), R01 CA130988 (W.C.H.), Department of Defense Idea Award W81XWH-07-1-0408 (W.C.H.), Dana-Farber Harvard Cancer Center SPORE in Breast Cancer P50 CA89393 (S.R.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. * E-mail: William_Hahn@dfci.harvard.edu . These authors contributed equally to this work.