CRK7 modifies the MAPK pathway and influences the response to endocrine therapy.

Full Abstract

Endocrine therapies, which inhibit estrogen receptor (ER)alpha signaling, are the most common and effective treatment for ERalpha-positive breast cancer. However, the use of these agents is limited by the frequent development of resistance. The cyclin-dependent kinase family member CRK7 (aka CRKRS) was identified from an RNA interference screen for modifiers of tamoxifen sensitivity. Here, we demonstrate that silencing of CRK7 not only causes resistance to tamoxifen but also leads to resistance to additional endocrine therapies including ICI 182780 and estrogen deprivation, a model of aromatase inhibition. We show that CRK7 silencing activates the mitogen-activated protein kinase (MAPK)-signaling pathway, which causes a loss of ER dependence, resulting in endocrine therapy resistance. This study identifies a novel role for CRK7 in MAPK regulation and resistance to estrogen signaling inhibitors.

Author information

Author/s: Iorns, Elizabeth (E); Martens-de Kemp, Sanne R (SR); Lord, Christopher J (CJ); Ashworth, Alan (A);

Affiliation: The Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, UK. eiorns(-atsign-)med.miami.edu

Journal and publication information

Publication Type: Journal Article; Research Support, Non-U.S. Gov't

Journal: Carcinogenesis (Carcinogenesis), published in England. (Language: eng)

Reference: 2009-Oct; vol 30 (issue 10) : pp 1696-701

Dates: Created 2009/10/06; Completed 2009/10/26;

PMID: 19651820, status: MEDLINE (last retrieval date: 10/26/2009, IMS Date: )

Sourced from the National Library of Medicine. Abstract text and other information may be subject to copyright.

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MeSH headings (categories)

This article was linked to the MESH Headings shown below.

Breast Neoplasms - pathology
Cell Cycle
Cell Division
Cell Line, Tumor
Cell Survival
Cyclin-Dependent Kinases - genetics; physiology
Estrogens - physiology
Female

Flow Cytometry
Gene Silencing
Humans
Mitogen-Activated Protein Kinases - metabolism
Polymerase Chain Reaction
RNA, Small Interfering - genetics
Retinoblastoma Protein - physiology
Tamoxifen - pharmacology

Associated Chemicals: Estrogens (0) ; RNA, Small Interfering (0) ; Retinoblastoma Protein (0) ; Tamoxifen (10540-29-1) ; Cyclin-Dependent Kinases (EC 2.7.1.37) ; Mitogen-Activated Protein Kinases (EC 2.7.1.37) ; CRKRS protein, human (EC 2.7.11.22)

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