CK1epsilon is required for breast cancers dependent on beta-catenin activity.

PLoS One
Authors
Keywords
Abstract

BACKGROUND: Aberrant beta-catenin signaling plays a key role in several cancer types, notably colon, liver and breast cancer. However approaches to modulate beta-catenin activity for therapeutic purposes have proven elusive to date.

METHODOLOGY: To uncover genetic dependencies in breast cancer cells that harbor active beta-catenin signaling, we performed RNAi-based loss-of-function screens in breast cancer cell lines in which we had characterized beta-catenin activity. Here we identify CSNK1E, the gene encoding casein kinase 1 epsilon (CK1epsilon) as required specifically for the proliferation of breast cancer cells with activated beta-catenin and confirm its role as a positive regulator of beta-catenin-driven transcription. Furthermore, we demonstrate that breast cancer cells that harbor activated beta-catenin activity exhibit enhanced sensitivity to pharmacological blockade of Wnt/beta-catenin signaling. We also find that expression of CK1epsilon is able to promote oncogenic transformation of human cells in a beta-catenin-dependent manner.

CONCLUSIONS/SIGNIFICANCE: These studies identify CK1epsilon as a critical contributor to activated beta-catenin signaling in cancer and suggest it may provide a potential therapeutic target for cancers that harbor active beta-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.

Year of Publication
2010
Journal
PLoS One
Volume
5
Issue
2
Pages
e8979
Date Published
2010 Feb 01
ISSN
1932-6203
URL
DOI
10.1371/journal.pone.0008979
PubMed ID
20126544
PubMed Central ID
PMC2813871
Links
Grant list
K08 CA134836 / CA / NCI NIH HHS / United States
R33 CA128625 / CA / NCI NIH HHS / United States
P50 CA089393 / CA / NCI NIH HHS / United States
K08 CA134836-01 / CA / NCI NIH HHS / United States
R01 CA130988 / CA / NCI NIH HHS / United States
P50 CA89393 / CA / NCI NIH HHS / United States
K08 CA100339 / CA / NCI NIH HHS / United States
P50 CA127003 / CA / NCI NIH HHS / United States