Epigenetic Regulation of Breast Cancer Progression by the Proto-oncogene PELP1

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DESCRIPTION (provided by applicant): Breast cancer is the second leading cause of cancer death in women. Estrogen and its target estrogen receptor alpha (ER¿), a master transcriptional regulator, are implicated in the initiation and progression of breast cancer. Endocrine therapies using tamoxifen and aromatase inhibitors substantially improve disease- free survival, however, initial or acquired resistance frequently occurs. While the molecular mechanism by which tumor cells modulate epigenetic changes at ER¿ target genes remains elusive, the deregulation of epigenetic modifiers may contribute to oncogenesis and therapy resistance. As a consequence, there is a critical need to understand the molecular mechanism(s) by which deregulation of epigenetic changes occurs during breast cancer progression. The transcriptional functions of ER¿ are influenced by several coactivators, including PELP1 and CARM1, that associate with histone modifying activities. PELP1 is an ER¿ coregulator and proto-oncogene with aberrant expression in hormone-related cancers and is an independent prognostic indicator of decreased survival in breast cancer patients. The molecular mechanism by which PELP1 promotes oncogenesis is not completely understood. My preliminary findings suggest that (1) PELP1 has the ability to recognize arginine di-methyl modified histone H3; (2) PELP1 interacts with the histone modifying enzyme CARM1; (3) PELP1 status affects CARM1 recruitment to ER¿ target genes and (4) PELP1 knockdown affects arginine methylation at ER¿ target genes. Based on these strong preliminary findings, I hypothesize that PELP1 interactions with CARM1 are crucial for PELP1 oncogenic functions and the PELP1-CARM1 axis determines the arginine methylation code at the ER¿ target genes leading to breast cancer progression. The objective of this proposal is to characterize the functional interaction of the PELP1 and CARM1 complex and determine the mechanism of epigenetic regulation of breast cancer progression by identifying the target genes and pathways. I will test my hypothesis using two specific aims. In Aim 1, I will test the significance of the PELP1-CARM1 axis in breast cancer by histone methyltransferase, reporter gene, proliferation and migration assays as well as a tumor tissue array. In Aim 2, I will determine the role of PELP1 regulation of the epigenome via arginine methylation by RNA- and ChIP-sequencing as well as ChIP, immunohistochemistry and qRTPCR analysis of murine tissues. Understanding the mechanism by which PELP1 modulates epigenetic changes and the reversible nature of these modifications provides a unique therapeutic opportunity to design novel drugs for treating hormonal cancers.