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Interference with ER‐α enhances the therapeutic efficacy of the selective CDK inhibitor roscovitine towards ER‐positive breast cancer cells
Author(s) -
WęsierskaGądek Józefa,
Gritsch David,
Zulehner Nora,
Komina Oxana,
Maurer Margarita
Publication year - 2011
Publication title -
journal of cellular biochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.028
H-Index - 165
eISSN - 1097-4644
pISSN - 0730-2312
DOI - 10.1002/jcb.23024
Subject(s) - cdk inhibitor , cyclin dependent kinase , estrogen receptor , cancer research , tamoxifen , palbociclib , selective estrogen receptor modulator , phosphorylation , kinase , breast cancer , cancer cell , estrogen , pharmacology , biology , cancer , chemistry , microbiology and biotechnology , medicine , endocrinology , cell cycle , metastatic breast cancer
In recent years many risk factors for the development of breast cancer that are linked to estrogens have been identified, and roscovitine (ROSC), a selective cyclin‐dependent kinase (CDK) inhibitor, has been shown to be an efficient inhibitor of the proliferation of human breast cancer cells. Therefore, we have examined the possibility that interference with estrogen signaling pathways, using tamoxifen (TAM), a selective estrogen receptor modulator (SERM), could modulate the efficacy of treatment with ROSC. In conjunction with TAM, ROSC exhibited enhanced anti‐proliferative activity and CDK inhibition, particularly in estrogen‐dependent MCF‐7 cells. The interaction between both drugs was synergistic. However, in ER‐α‐negative cells the interaction was antagonistic. Exposure of MCF‐7 cells to ROSC abolished the activating phosphorylation of CDK2 and CDK7 at Ser 164/170 . This in turn prevented the phosphorylation of the carboxyl‐terminal repeat domain of RNA Polymerase II and ER‐α at Ser 118 , resulting in the down‐regulation of the latter. Concomitantly, wt p53 was strongly activated by phosphorylation at Ser 46 . Our results demonstrate that ROSC negatively affects the functional status of ER‐α, making it potentially useful in the treatment of estrogen‐dependent breast cancer cells. J. Cell. Biochem. 112: 1103–1117, 2011. © 2011 Wiley‐Liss, Inc.