Evaluating the Significance of CDK2-PELP1 Axis in Tumorigenesis and Hormone Therapy Resistance

Abstract

Abstract : Current endocrine therapy for ER+ve breast cancer involves Tamoxifen, and Aromatase inhibitors. De novoand/or acquired resistance to endocrine therapies however frequently occur. Interestingly, earlier studies have shown that activation of Cyclin Dependent Kinase 2 (CDK2) and deregulation of PELP1 (Proline, glutamic Acid and Leucine rich Protein), a novel ER coregulator is found associated with endocrine therapy resistance. The results of this study showed that PELP1 is a novel substrate of CDK2. Functional studies established PELP1 as a modulator of E2F transactivation function and PELP1 phosphorylation is needed for optimal activation of E2F target genes. Studies utilizing a novel PELP1 phospho antibody, model cell lines stably expressing the PELP1-shRNA or PELP1-CDK2 phosphosite mutants demonstrated that CDK phosphorylation of PELP1 is important for estrogen (E2) mediated cell cycle progression. Further, PELP1 phosphorylation by CDK is important for E2-mediated tumorigenesis in vivo and deregulation of CDKPELP1 axis was observed in various endocrine resistant model breast cancer cells. Blocking CDK2 activation using Roscovitine, a drug currently in clinical trials, confers tumor suppressive effects. Further, Roscovitine has the potential to alter the ER alpha/beta ratio in breast cancer cells. Overall, these results suggest that CDK phosphorylation of PELP1 is important for E2 driven cell cycle progression and blocking CDK2-PELP1 axis activation by Roscovitine will have therapeutic implications.