Role of lysine methylation in estrogen receptor function and tamoxifen response

Emory University, Atlanta GA

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Abstract

DESCRIPTION (provided by applicant): Breast cancer is the leading cancer diagnosis among US women. The antiestrogen therapy tamoxifen has been a mainline therapy for breast cancer for the 70% of women whose tumors are estrogen receptor alpha (ER) positive for over thirty years. The ER pathway is essential for normal cell breast development, but can also promote growth of breast cancer. Targeting this pathway with tamoxifen abrogates this growth signal. However, the use of tamoxifen has been limited by resistance (both intrinsic and de novo) to this therapy. The mechanism by which tamoxifen resistance develops is not yet understood. One putative model for the development of tamoxifen resistance is that post-translational modifications to ER, possibly through increased crosstalk between ER and growth factor receptors, can change the ER-ligand interaction and alter tamoxifen response. For instance, phosphorylation of ER serine 305 (S305P) is associated with tamoxifen resistance in both cell culture models and in primary breast tumor samples. Previous work in our lab discovered that ER can be methylated at lysine 302 (K302me) by the histone methyltransferase Set7. K302 methylation stabilizes ER and promotes transcription of ER target genes. Whether K302me influences S305P or vice versa to regulate ER activity is not known. Likewise, the role of K302me in response to tamoxifen has not yet been investigated. K302me may influence ER activity by providing a novel epitope recognized by ER co-factors. From a protein binding screen, we have identified a domain of PHD finger 20 Like 1 (PHF20L1) that selectively binds to ER peptides methylated at K302. The precise function of PHF20L1 is not known, but PHF20L1 has been found to be translocated in breast cancer cell lines and to be overexpressed in ovarian tumors. The interaction between PHF20L1 and ER still needs to be characterized. We hypothesize that the balance between methylation and phosphorylation of ER regulates ER activity, including the recruitment of co-factor PHF20L1 and sensitivity to tamoxifen. In our first aim, we will determine the impact of K302me on PHF20L1 recruitment and ER driven transcription. In our second aim, we will determine the relationship between ER K302 methylation and S305 phosphorylation. In our third aim, we will establish how K302me affects tamoxifen sensitivity. Our long term goal is to determine the mechanism of tamoxifen resistance. By determining how K302me alters ER activity, we may significantly advance our understanding of ER regulation and tamoxifen response. Our work with ER regulation has the potential to discover new targets for drug therapy, like Set7 or PHF20L1, to combat tamoxifen resistance and could inform how of current therapies are used.