Abstract | INTRODUCTION: METHODS: Using various in vitro and in vivo assays, we tested the effect of roscovitine on three hormonal therapy-resistant model cells: (a) MCF-7-TamR (acquired tamoxifen resistance model); (b) MCF-7-LTLTca (acquired letrozole resistance model); and (c) MCF-7-HER2 that exhibit tamoxifen resistance (ER- growth factor signaling cross talk model). RESULTS: Hormonal therapy-resistant cells exhibited aberrant activation of the CDK2 pathway. Roscovitine at a dose of 20 μM significantly inhibited the cell proliferation rate and foci formation potential of all three therapy-resistant cells. The drug treatment substantially increased the proportion of cells in G2/M cell cycle phase with decreased CDK2 activity and promoted low cyclin D1 levels. Interestingly, roscovitine also preferentially down regulated the ERα isoform and ER-coregulators including AIB1 and PELP1. Results from xenograft studies further showed that roscovitine can attenuate growth of therapy-resistant tumors in vivo. CONCLUSIONS:
Roscovitine can reduce cell proliferation and survival of hormone therapy-resistant breast cancer cells. Our results support the emerging concept that inhibition of CDK2 activity has the potential to abrogate growth of hormonal therapy-resistant cells.
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Authors | Binoj C Nair, Sreeram Vallabhaneni, Rajeshwar R Tekmal, Ratna K Vadlamudi |
Journal | Breast cancer research : BCR
(Breast Cancer Res)
Vol. 13
Issue 3
Pg. R80
(Aug 11 2011)
ISSN: 1465-542X [Electronic] England |
PMID | 21834972
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)
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Chemical References |
- Antineoplastic Agents, Hormonal
- Co-Repressor Proteins
- ESR1 protein, human
- Estrogen Receptor alpha
- PELP1 protein, human
- Protein Kinase Inhibitors
- Purines
- Transcription Factors
- Roscovitine
- Cyclin D1
- NCOA3 protein, human
- Nuclear Receptor Coactivator 3
- CDK2 protein, human
- Cyclin-Dependent Kinase 2
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Topics |
- Animals
- Antineoplastic Agents, Hormonal
(pharmacology)
- Breast Neoplasms
(drug therapy)
- Cell Cycle
(drug effects)
- Cell Line, Tumor
- Cell Proliferation
(drug effects)
- Co-Repressor Proteins
(biosynthesis, drug effects)
- Cyclin D1
(drug effects)
- Cyclin-Dependent Kinase 2
(antagonists & inhibitors, metabolism)
- Drug Resistance, Neoplasm
(drug effects)
- Estrogen Receptor alpha
(metabolism)
- Female
- Humans
- Mice
- Mice, Nude
- Nuclear Receptor Coactivator 3
(metabolism)
- Protein Kinase Inhibitors
(pharmacology)
- Purines
(pharmacology)
- Roscovitine
- Transcription Factors
(biosynthesis, drug effects)
- Xenograft Model Antitumor Assays
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