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| Status |
Public on Aug 30, 2019 |
| Title |
Short and long-term effects of CDK4/6 inhibition on early stage breast cancer |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
CDK4/6 inhibitors are used in the treatment of advanced estrogen receptor (ER)(+) breast cancer (BC). Their efficacy in ER(-) and early stage BC is currently under investigation. Here, we show that palbociclib, a CDK4/6 inhibitor, can inhibit both progression of ductal carcinoma in situ (DCIS) and growth of invasive disease in both an ER(-) basal BC model (MCFDCIS) and an ER(+) luminal model (MCF7 intraductal injection). In MCFDCIS cells palbociclib repressed cell cycle gene expression, inhibited proliferation, induced senescence and normalized tumorspheres formed in Matrigel whilst the formation of acini by normal mammary epithelial cells (MCF10A) was not affected. Palbociclib treatment of mice with MCFDCIS tumors inhibited their malignant progression and reduced proliferation of invasive lesions. Transcriptomic analysis of the tumor and stromal cell compartments showed that cell cycle and senescence genes, and MUC16, an ovarian cancer biomarker gene, were repressed during treatment. Knockdown of MUC16 in MCFDCIS cells inhibited proliferation of invasive lesions but not progression of DCIS. After cessation of palbociclib treatment genes associated with differentiation, e.g. p63, inflammation, IFNγ response and antigen processing and presentation remained suppressed in the tumor and surrounding stroma. We conclude that palbociclib can prevent progression of DCIS and is anti-proliferative in ER(-) invasive disease mediated in part via MUC16. Lasting effects of CDK4/6 inhibition after drug withdrawal on differentiation and the immune response could impact the approach to treatment of early stage ER(-) breast cancer.
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| Overall design |
3 Tumor Replicates/group. 4 Groups - 2wk Palbociclib, 2wk Vehicle, 2wk Palbociclib + Recovery and 2wk Vehicle + Recovery. Vehicle treated tumors were used as baseline for comparisons and interrogation of drug effects.
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| Contributor(s) |
Kietzman WB, Graham GT, Ory V, Sharif G, Kushner MH, Gallanis GT, Kallakury BV, Wellstein A, Riegel AT |
| Citation(s) |
31451564 |
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| Submission date |
May 08, 2019 |
| Last update date |
Dec 01, 2019 |
| Contact name |
Garrett Thomas Graham |
| E-mail(s) |
gtg9@georgetown.edu
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| Phone |
8148822017
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| Organization name |
Georgetown University Medical Center
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| Department |
Oncology
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| Street address |
3970 Reservoir Rd NW
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| City |
Washington |
| State/province |
DC |
| ZIP/Postal code |
20007 |
| Country |
USA |
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| Platforms (1) |
| GPL11154 |
Illumina HiSeq 2000 (Homo sapiens) |
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| Samples (12)
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| GSM3755986 |
MCFDCIS tumor treated with palbociclib, initial response (2T-711L) |
| GSM3755987 |
MCFDCIS tumor treated with palbociclib, initial response (2T-712R) |
| GSM3755988 |
MCFDCIS tumor treated with palbociclib, initial response (2T-714R) |
| GSM3755989 |
MCFDCIS tumor treated with palbociclib, recovery response (2TR-701R) |
| GSM3755990 |
MCFDCIS tumor treated with palbociclib, recovery response (2TR-703R) |
| GSM3755991 |
MCFDCIS tumor treated with palbociclib, recovery response (2TR-705L) |
| GSM3755992 |
MCFDCIS tumor treated with vehicle, initial response (2V-096L) |
| GSM3755993 |
MCFDCIS tumor treated with vehicle, initial response (2V-717L) |
| GSM3755994 |
MCFDCIS tumor treated with vehicle, initial response (2V-720R) |
| GSM3755995 |
MCFDCIS tumor treated with vehicle, recovery response (2VR-1081L) |
| GSM3755996 |
MCFDCIS tumor treated with vehicle, recovery response (2VR-1092L) |
| GSM3755997 |
MCFDCIS tumor treated with vehicle, recovery response (2VR-709R) |
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| Relations |
| BioProject |
PRJNA541931 |
| SRA |
SRP197105 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE130903_RAW.tar |
4.4 Mb |
(http)(custom) |
TAR (of TXT) |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data provided as supplementary file |
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