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

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.

• Authors: So Young Kim, Ian F Dunn, Ron Firestein, Piyush Gupta, Leslie Wardwell, Kara Repich, Anna C Schinzel, Ben Wittner, Serena J Silver, David E Root, Jesse S Boehm, Sridhar Ramaswamy, Eric S Lander, William C Hahn
• Journal: PloS one (PLoS One) Vol. 5 Issue 2 Pg. e8979 (Feb 01 2010) ISSN: 1932-6203 [Electronic] United States
• PMID: 20126544 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• IC 261
• Indoles
• beta Catenin
• Phloroglucinol
• Casein Kinase 1 epsilon

Topics

• Animals
• Breast Neoplasms (genetics, metabolism, pathology)
• Casein Kinase 1 epsilon (antagonists & inhibitors, genetics, metabolism)
• Cell Line
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cell Transformation, Neoplastic (drug effects)
• Dose-Response Relationship, Drug
• Gene Expression Profiling
• Gene Expression Regulation, Neoplastic
• Humans
• Immunoblotting
• Indoles (pharmacology)
• Mice
• NIH 3T3 Cells
• Oligonucleotide Array Sequence Analysis
• Phloroglucinol (analogs & derivatives, pharmacology)
• RNA Interference
• Signal Transduction
• beta Catenin (genetics, metabolism)