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The relationship of CDK18 expression in breast cancer to clinicopathological parameters and therapeutic response

The relationship of CDK18 expression in breast cancer to clinicopathological parameters and therapeutic response
The relationship of CDK18 expression in breast cancer to clinicopathological parameters and therapeutic response
Background: Cyclin-Dependent Kinases (CDKs) are established anti-cancer drug targets and a new generation of CDK inhibitors are providing clinical benefits to a sub-set of breast cancer patients. We have recently shown that human CDK18 promotes efficient cellular responses to replication stress. In the current study, we have investigated the clinicopathological and functional significance of CDK18 expression levels in breast cancers.

Results: high CDK18 protein expression was associated with a triple negative and basal-like phenotype (p = 0.021 and 0.027 respectively) as well as improved patient survival, which was particularly significant in ER negative breast cancers (n = 594, Log Rank 6.724, p = 0.01) and those treated with chemotherapy (n = 270, Log Rank 4.575, p = 0.03). In agreement with these clinical findings, breast cancer cells genetically manipulated using a dCRISPR approach to express high levels of endogenous CDK18 exhibited an increased sensitivity to replication stress-inducing chemotherapeutic agents, as a consequence to defective replication stress signalling at the molecular level.

Materials and Methods: CDK18 protein expression was evaluated in 1650 breast cancers and correlated to clinicopathological parameters and survival outcomes. Similar analyses were carried out for genetic and transcriptomic changes in CDK18 within several publically available breast cancer cohorts. Additionally, we used a deactivated CRISPR/Cas9 approach (dCRISPR) to elucidate the molecular consequences of heightened endogenous CDK18 expression within breast cancer cells.

Conclusions: these data reveal that CDK18 protein levels may predict breast cancer disease progression and response to chemotherapy, and provide further rationale for potential targeting of CDK18 as part of novel anti-cancer strategies for human cancers.
1949-2553
29508-29524
Barone, Giancarlo
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Arora, Arvind
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Ganesh, Anil
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Abdel-fatah, Tarek
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Moseley, Paul
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Ali, Reem
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Chan, Stephen Yt
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Savva, Constantinos
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Schiavone, Kristina
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Carmell, Natasha
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Myers, Katie N.
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Rakha, Emad A.
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Madhusudan, Srinivasan
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Collis, Spencer J.
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Barone, Giancarlo
282e1a6f-0115-424f-92d9-11bb0fb2f11c
Arora, Arvind
f557b663-05bf-40ad-951b-9533cd84c403
Ganesh, Anil
c65044c5-81a7-4d11-8629-81395d3f2871
Abdel-fatah, Tarek
11a0dd0a-4a99-4690-a3d3-1ee0cdf24743
Moseley, Paul
8e06e9c3-fce2-4676-ae0f-de61e1d79929
Ali, Reem
1b6ef7ba-f807-4cd7-8455-039ca8eb8e73
Chan, Stephen Yt
b372a6e5-2fad-473c-b89b-eb48febe3907
Savva, Constantinos
d6e87674-1443-41f4-84ba-81c1ccfeb3d7
Schiavone, Kristina
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Carmell, Natasha
1af671b9-d315-4d96-b53d-e03ea17cff16
Myers, Katie N.
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Rakha, Emad A.
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Madhusudan, Srinivasan
b09d6e47-8c8f-484f-83cf-e77c2de21952
Collis, Spencer J.
b648703b-55e5-4a70-a18f-9e69bcb98024

Barone, Giancarlo, Arora, Arvind, Ganesh, Anil, Abdel-fatah, Tarek, Moseley, Paul, Ali, Reem, Chan, Stephen Yt, Savva, Constantinos, Schiavone, Kristina, Carmell, Natasha, Myers, Katie N., Rakha, Emad A., Madhusudan, Srinivasan and Collis, Spencer J. (2018) The relationship of CDK18 expression in breast cancer to clinicopathological parameters and therapeutic response. Oncotarget, 9 (50), 29508-29524. (doi:10.18632/oncotarget.v9i50).

Record type: Article

Abstract

Background: Cyclin-Dependent Kinases (CDKs) are established anti-cancer drug targets and a new generation of CDK inhibitors are providing clinical benefits to a sub-set of breast cancer patients. We have recently shown that human CDK18 promotes efficient cellular responses to replication stress. In the current study, we have investigated the clinicopathological and functional significance of CDK18 expression levels in breast cancers.

Results: high CDK18 protein expression was associated with a triple negative and basal-like phenotype (p = 0.021 and 0.027 respectively) as well as improved patient survival, which was particularly significant in ER negative breast cancers (n = 594, Log Rank 6.724, p = 0.01) and those treated with chemotherapy (n = 270, Log Rank 4.575, p = 0.03). In agreement with these clinical findings, breast cancer cells genetically manipulated using a dCRISPR approach to express high levels of endogenous CDK18 exhibited an increased sensitivity to replication stress-inducing chemotherapeutic agents, as a consequence to defective replication stress signalling at the molecular level.

Materials and Methods: CDK18 protein expression was evaluated in 1650 breast cancers and correlated to clinicopathological parameters and survival outcomes. Similar analyses were carried out for genetic and transcriptomic changes in CDK18 within several publically available breast cancer cohorts. Additionally, we used a deactivated CRISPR/Cas9 approach (dCRISPR) to elucidate the molecular consequences of heightened endogenous CDK18 expression within breast cancer cells.

Conclusions: these data reveal that CDK18 protein levels may predict breast cancer disease progression and response to chemotherapy, and provide further rationale for potential targeting of CDK18 as part of novel anti-cancer strategies for human cancers.

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Accepted/In Press date: 13 June 2018
Published date: 29 June 2018

Identifiers

Local EPrints ID: 424102
URI: https://eprints.soton.ac.uk/id/eprint/424102
ISSN: 1949-2553
PURE UUID: d5e723b7-0b9b-46d4-887b-5ad9d16a3aa5
ORCID for Constantinos Savva: ORCID iD orcid.org/0000-0003-0805-4719

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Date deposited: 04 Oct 2018 16:30
Last modified: 14 Mar 2019 01:22

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Contributors

Author: Giancarlo Barone
Author: Arvind Arora
Author: Anil Ganesh
Author: Tarek Abdel-fatah
Author: Paul Moseley
Author: Reem Ali
Author: Stephen Yt Chan
Author: Kristina Schiavone
Author: Natasha Carmell
Author: Katie N. Myers
Author: Emad A. Rakha
Author: Srinivasan Madhusudan
Author: Spencer J. Collis

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