Abstract
IntroductionCurrent 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.MethodsUsing 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).ResultsHormonal 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.ConclusionsRoscovitine 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.
Highlights
Current clinical strategies for treating hormonal breast cancer involve the use of anti-estrogens that block estrogen receptor (ER)a functions and aromatase inhibitors that decrease local and systemic estrogen production
Most downstream events in these resistance signaling pathways converge upon modulation of cell cycle regulatory proteins; the most conspicuous of which is the upregulation of cyclins E and A, along with activation of cyclin dependent kinase 2 (CDK2) [9,10]
ERa was purchased from Santa Cruz Biotechnology (Santa Cruz, CA, USA) and Thermo Fisher Scientific (Rockford, IL, USA). terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) kit for apoptosis detection was purchased from (Roche, Mannheim, Germany) and Proliferating Cell Nuclear Antigen (PCNA) antibody was purchased from Vector Lab (Burlingame, CA, USA)
Summary
Current clinical strategies for treating hormonal breast cancer involve the use of anti-estrogens that block estrogen receptor (ER)a functions and aromatase inhibitors that decrease local and systemic estrogen production Both of these strategies improve outcomes for ERa-positive breast cancer patients, development of therapy resistance remains a major clinical problem. The expression of RB/E2F target genes, which is tightly controlled by CDK2 activity, is often deregulated and associated with worse prognosis for tamoxifen-treated breast cancer patients [15] These emerging studies strongly support the concept that CDK2 activity is a critical component for the generation of a hormone therapy-resistant phenotype and that blocking of CDK2 activity may be useful as a therapeutic strategy for therapy-resistant patients
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