CK1ε is required for breast cancers dependent on β-catenin activity

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

Research output: Contribution to journalArticleResearchpeer-review

36 Citations (Scopus)

Abstract

Background: Aberrant β-catenin signaling plays a key role in several cancer types, notably colon, liver and breast cancer. However approaches to modulate β-catenin activity for therapeutic purposes have proven elusive to date. Methodology: To uncover genetic dependencies in breast cancer cells that harbor active β-catenin signaling, we performed RNAi-based loss-of-function screens in breast cancer cell lines in which we had characterized β-catenin activity. Here we identify CSNK1E, the gene encoding casein kinase 1 epsilon (CK1ε) as required specifically for the proliferation of breast cancer cells with activated β-catenin and confirm its role as a positive regulator of β-catenin-driven transcription. Furthermore, we demonstrate that breast cancer cells that harbor activated β-catenin activity exhibit enhanced sensitivity to pharmacological blockade of Wnt/β-catenin signaling. We also find that expression of CK1ε is able to promote oncogenic transformation of human cells in a β-catenin-dependent manner. Conclusions/Significance: These studies identify CK1ε as a critical contributor to activated β-catenin signaling in cancer and suggest it may provide a potential therapeutic target for cancers that harbor active β-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.

Original languageEnglish
Article numbere8979
Number of pages10
JournalPLoS ONE
Volume5
Issue number2
DOIs
Publication statusPublished - 1 Feb 2010
Externally publishedYes

Cite this

Kim, S. Y., Dunn, I. F., Firestein, R., Gupta, P., Wardwell, L., Repich, K., ... Hahn, W. C. (2010). CK1ε is required for breast cancers dependent on β-catenin activity. PLoS ONE, 5(2), [e8979]. https://doi.org/10.1371/journal.pone.0008979
Kim, So Young ; Dunn, Ian F. ; Firestein, Ron ; Gupta, Piyush ; Wardwell, Leslie ; Repich, Kara ; Schinzel, Anna C. ; Wittner, Ben ; Silver, Serena J. ; Root, David E. ; Boehm, Jesse S ; Ramaswamy, Sridhar ; Lander, Eric S ; Hahn, William C. / CK1ε is required for breast cancers dependent on β-catenin activity. In: PLoS ONE. 2010 ; Vol. 5, No. 2.
@article{2104bda5cf45452b9d57dd40f81db7e2,
title = "CK1ε is required for breast cancers dependent on β-catenin activity",
abstract = "Background: Aberrant β-catenin signaling plays a key role in several cancer types, notably colon, liver and breast cancer. However approaches to modulate β-catenin activity for therapeutic purposes have proven elusive to date. Methodology: To uncover genetic dependencies in breast cancer cells that harbor active β-catenin signaling, we performed RNAi-based loss-of-function screens in breast cancer cell lines in which we had characterized β-catenin activity. Here we identify CSNK1E, the gene encoding casein kinase 1 epsilon (CK1ε) as required specifically for the proliferation of breast cancer cells with activated β-catenin and confirm its role as a positive regulator of β-catenin-driven transcription. Furthermore, we demonstrate that breast cancer cells that harbor activated β-catenin activity exhibit enhanced sensitivity to pharmacological blockade of Wnt/β-catenin signaling. We also find that expression of CK1ε is able to promote oncogenic transformation of human cells in a β-catenin-dependent manner. Conclusions/Significance: These studies identify CK1ε as a critical contributor to activated β-catenin signaling in cancer and suggest it may provide a potential therapeutic target for cancers that harbor active β-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.",
author = "Kim, {So Young} and Dunn, {Ian F.} and Ron Firestein and Piyush Gupta and Leslie Wardwell and Kara Repich and Schinzel, {Anna C.} and Ben Wittner and Silver, {Serena J.} and Root, {David E.} and Boehm, {Jesse S} and Sridhar Ramaswamy and Lander, {Eric S} and Hahn, {William C.}",
year = "2010",
month = "2",
day = "1",
doi = "10.1371/journal.pone.0008979",
language = "English",
volume = "5",
journal = "PLoS ONE",
issn = "1932-6203",
publisher = "Public Library of Science",
number = "2",

}

Kim, SY, Dunn, IF, Firestein, R, Gupta, P, Wardwell, L, Repich, K, Schinzel, AC, Wittner, B, Silver, SJ, Root, DE, Boehm, JS, Ramaswamy, S, Lander, ES & Hahn, WC 2010, 'CK1ε is required for breast cancers dependent on β-catenin activity', PLoS ONE, vol. 5, no. 2, e8979. https://doi.org/10.1371/journal.pone.0008979

CK1ε is required for breast cancers dependent on β-catenin activity. / Kim, So Young; Dunn, Ian F.; Firestein, Ron; Gupta, Piyush; Wardwell, Leslie; Repich, Kara; Schinzel, Anna C.; Wittner, Ben; Silver, Serena J.; Root, David E.; Boehm, Jesse S; Ramaswamy, Sridhar; Lander, Eric S; Hahn, William C.

In: PLoS ONE, Vol. 5, No. 2, e8979, 01.02.2010.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - CK1ε is required for breast cancers dependent on β-catenin activity

AU - Kim, So Young

AU - Dunn, Ian F.

AU - Firestein, Ron

AU - Gupta, Piyush

AU - Wardwell, Leslie

AU - Repich, Kara

AU - Schinzel, Anna C.

AU - Wittner, Ben

AU - Silver, Serena J.

AU - Root, David E.

AU - Boehm, Jesse S

AU - Ramaswamy, Sridhar

AU - Lander, Eric S

AU - Hahn, William C.

PY - 2010/2/1

Y1 - 2010/2/1

N2 - Background: Aberrant β-catenin signaling plays a key role in several cancer types, notably colon, liver and breast cancer. However approaches to modulate β-catenin activity for therapeutic purposes have proven elusive to date. Methodology: To uncover genetic dependencies in breast cancer cells that harbor active β-catenin signaling, we performed RNAi-based loss-of-function screens in breast cancer cell lines in which we had characterized β-catenin activity. Here we identify CSNK1E, the gene encoding casein kinase 1 epsilon (CK1ε) as required specifically for the proliferation of breast cancer cells with activated β-catenin and confirm its role as a positive regulator of β-catenin-driven transcription. Furthermore, we demonstrate that breast cancer cells that harbor activated β-catenin activity exhibit enhanced sensitivity to pharmacological blockade of Wnt/β-catenin signaling. We also find that expression of CK1ε is able to promote oncogenic transformation of human cells in a β-catenin-dependent manner. Conclusions/Significance: These studies identify CK1ε as a critical contributor to activated β-catenin signaling in cancer and suggest it may provide a potential therapeutic target for cancers that harbor active β-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.

AB - Background: Aberrant β-catenin signaling plays a key role in several cancer types, notably colon, liver and breast cancer. However approaches to modulate β-catenin activity for therapeutic purposes have proven elusive to date. Methodology: To uncover genetic dependencies in breast cancer cells that harbor active β-catenin signaling, we performed RNAi-based loss-of-function screens in breast cancer cell lines in which we had characterized β-catenin activity. Here we identify CSNK1E, the gene encoding casein kinase 1 epsilon (CK1ε) as required specifically for the proliferation of breast cancer cells with activated β-catenin and confirm its role as a positive regulator of β-catenin-driven transcription. Furthermore, we demonstrate that breast cancer cells that harbor activated β-catenin activity exhibit enhanced sensitivity to pharmacological blockade of Wnt/β-catenin signaling. We also find that expression of CK1ε is able to promote oncogenic transformation of human cells in a β-catenin-dependent manner. Conclusions/Significance: These studies identify CK1ε as a critical contributor to activated β-catenin signaling in cancer and suggest it may provide a potential therapeutic target for cancers that harbor active β-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.

UR - http://www.scopus.com/inward/record.url?scp=77749258756&partnerID=8YFLogxK

U2 - 10.1371/journal.pone.0008979

DO - 10.1371/journal.pone.0008979

M3 - Article

C2 - 20126544

AN - SCOPUS:77957319321

VL - 5

JO - PLoS ONE

JF - PLoS ONE

SN - 1932-6203

IS - 2

M1 - e8979

ER -