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Roscovitine confers tumor suppressive effect on therapy-resistant breast tumor cells
Binoj C Nair1, Sreeram Vallabhaneni, Rajeshwar R Tekmal
1Department of Obstetrics and Gynecology, CTRC at UT Health Science Center, San Antonio, Texas 78229, USA.
Introduction:
Current clinical strategies for treating hormonal breast cancer involve the use of anti-estrogens that block estrogen receptor (ER)α functions and aromatase inhibitors that decrease local and systemic estrogen production. Both of these strategies improve outcomes for ERα-positive breast cancer patients, however, development of therapy resistance remains a major clinical problem. Divergent molecular pathways have been described for this resistant phenotype and interestingly, the majority of downstream events in these resistance pathways converge upon the modulation of cell cycle regulatory proteins including aberrant activation of cyclin dependent kinase 2 (CDK2). In this study, we examined whether the CDK inhibitor roscovitine confers a tumor suppressive effect on therapy-resistant breast epithelial cells.
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 microM 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.
Insights
Roscovitine, a CDK inhibitor, effectively reduces proliferation and survival in hormone therapy-resistant breast cancer cells by targeting the CDK2 pathway. This suggests CDK2 inhibition is a promising strategy for overcoming treatment resistance.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Hormonal therapies (anti-estrogens, aromatase inhibitors) are standard for ERα-positive breast cancer but face challenges with therapy resistance.
- Therapy resistance in breast cancer involves complex molecular pathways, often converging on cell cycle dysregulation, particularly aberrant cyclin-dependent kinase 2 (CDK2) activation.
Purpose of the Study:
- To investigate the anti-cancer effects of the CDK inhibitor roscovitine on hormone therapy-resistant breast cancer cells.
- To determine if targeting CDK2 activity can overcome resistance mechanisms in breast cancer.
Main Methods:
- In vitro assays were used to test roscovitine's effects on three distinct models of hormone therapy-resistant breast cancer cells (tamoxifen-resistant, letrozole-resistant, and ER-growth factor signaling cross-talk resistant).
- In vivo xenograft studies were conducted to evaluate roscovitine's efficacy in a tumor model.
Main Results:
- Roscovitine (20 microM) significantly inhibited proliferation and foci formation in all tested resistant cell lines.
- The drug induced G2/M cell cycle arrest, decreased CDK2 activity, and lowered cyclin D1 levels.
- Roscovitine downregulated ERα, AIB1, and PELP1, and in vivo studies showed tumor growth attenuation.
Conclusions:
- Roscovitine demonstrates significant tumor suppressive effects on hormone therapy-resistant breast cancer cells.
- Inhibition of CDK2 activity represents a viable therapeutic strategy to combat resistance in hormonal breast cancer.
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