Evaluating the Significance of CDK2-PELP1 Axis in Tumorigenesis and Hormone Therapy Resistance
Abstract
The estrogen receptor (ER) plays a central role in the progression of breast cancer. Current endocrine therapy for ER+ve breast cancer involves Tamoxifen, and Aromatase inhibitors. De novo and/or acquired resistance to endocrine therapies however occurs frequently. Interestingly, most downstream events in these resistance signaling pathways converge upon modulation of cell cycle regulatory proteins, including upregulation of Cyclin E and A with activation of Cyclin Dependent Kinase 2 (CDK2). PELP1 (Proline, glutamic Acid and Leucine rich Protein) is a novel ER coregulator that has deregulated expression and localization in breast cancer. In the first year of grant support from DODBCMRP, we have found that PELP1 is a novel substrate of CDK2 and that its phosphorylation is important for estrogen mediated cell cycle progression using ZR75 model cells that harbors over-expressed dominant PELP1-CDK2 site mutant. We have also developed the first ever phosphoantibody against PELP1 to study its phosphorylation status and function in cell cycle progression and tumorigenesis. We also found that PELP1 can E2F transactivation function and future studies will include investigating the role of CDK2 mediated phosphorylation of PELP1 in epigenetic modulation of E2F and ER target genes, and thereby in PELP1 mediated tumorigenesis. In further we intend to characterize the CDK2?PELP1 axis in hormone therapy resistance.
Document Details
- Document Type
- Technical Report
- Publication Date
- Feb 01, 2010
- Accession Number
- ADA542787
Entities
People
- Binoj Nair
Organizations
- University of Texas Health Science Center at San Antonio