|
| Status |
Public on Feb 08, 2017 |
| Title |
High CDK6 protects cells from fulvestrant-mediated apoptosis and is a predictor of resistance to fulvestrant in estrogen receptor-positive metastatic breast cancer |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by array
|
| Summary |
Purpose: Resistance to endocrine therapy in estrogen receptor-positive (ER+) breast cancer remains a major clinical problem. Recently, the CDK4/6 inhibitor palbociclib combined with letrozole was approved for treatment of ER+ advanced breast cancer, and other CDK4/6 inhibitors are being investigated in combination with different endocrine treatments. However, the role of CDK4/6 in endocrine resistance and their potential as predictive biomarkers of endocrine treatment response remains undefined.
Experimental Design: We investigated the specific role of increased CDK6 expression in fulvestrant-resistant cells by gene knockdown and treatment with palbociclib, and evaluated the effect in cell proliferation, apoptosis and kinase activity. Furthermore, we evaluated CDK6 expression in metastatic samples from breast cancer patients treated or not with fulvestrant.
Results: We found increased expression of CDK6 in two fulvestrant-resistant cell models vs. sensitive cells. Reduction of CDK6 expression impaired fulvestrant-resistant cell growth and induced apoptosis by reducing p70 ribosomal S6 kinase 2 activity. Treatment with palbociclib re-sensitized fulvestrant-resistant cells to fulvestrant through alteration of retinoblastoma phosphorylation. High CDK6 levels in metastatic samples from breast cancer patients treated with fulvestrant (N=45) correlated significantly with shorter progression-free survival (PFS) (p=0.0006), while no association was observed in patients receiving other endocrine treatments (N=41, p=0.874).
Conclusions: Our results indicate that upregulation of CDK6 may be an important mechanism in overcoming fulvestrant-mediated growth inhibition in breast cancer cells. Patients with advanced ER+ breast cancer exhibiting high CDK6 expression in the metastatic lesions show shorter PFS upon fulvestrant treatment and thus may benefit from the addition of CDK4/6 inhibitors in their therapeutic regimens.
|
| |
|
| Overall design |
The array included 20 fulvestrant resistant MCF7 cell lines named as ICI182 and ICI164 and 6 fulvestrant sensitive MCF7/S0.5. Ten biological replicates of each of ICI182 and ICI164 as well as 6biological replicates of parental fulvestrant sensitive cell lines were used in the study.
|
| |
|
| Contributor(s) |
Elias D, Alves C, Lyng M, Bak M, Lykkesfeldt AE, Ditzel HJ |
| Citation(s) |
27252418, 36153348 |
| |
| Submission date |
Oct 27, 2015 |
| Last update date |
Oct 21, 2022 |
| Contact name |
Daniel Elias |
| E-mail(s) |
[email protected]
|
| Organization name |
University of Southern Denmark
|
| Department |
Cancer and Inflammation Research
|
| Lab |
Ditzel Lab
|
| Street address |
J. B. Winsløwsvej 25
|
| City |
Odense C |
| ZIP/Postal code |
5000 |
| Country |
Denmark |
| |
|
| Platforms (1) |
| GPL570 |
[HG-U133_Plus_2] Affymetrix Human Genome U133 Plus 2.0 Array |
|
| Samples (26)
|
|
| Relations |
| BioProject |
PRJNA300266 |
Less...
More...