REGULATION OF ER-BETA SIGNALING IN CARCINOGENESIS

Estrogen receptor (ER)? exhibits an antitumor activity in multiple cancer types in both tumor-intrinsicand -extrinsic manners. However, little is known as to how such activity can be harnessed with high efficacyand precision, nor is it clear which host cell type(s) mediates the tumor-extrinsic function of ER?. These majorknowledge gaps hamper efforts to unleash ER? antitumor activity for cancer therapies. We recently discovereda phosphotyrosine-dependent signaling axis that controls ER? antitumor activity. Furthermore, using a novelknockin mouse model, we found that this phosphotyrosine switch plays a significant role in host cells topromote antitumor immunity. Our central hypothesis is that this ER?-centered signaling axis provides apreviously unrecognized molecular handle for mobilizing tumor-extrinsic antitumor activity of ER? inimmune cells. Armed with genetic and pharmacological tools that both specifically target this signaling circuit,our multi-PI team will validate this novel hypothesis through three Specific Aims. First, we will identify the exactimmune cell type(s) that mediates tumor-extrinsic ER? signaling in antitumor immunity (Aim 1). We will thendelineate the upstream regulators and downstream target genes of ER? signaling in immune cells (Aim 2).Lastly, we will assess the anticancer therapeutic potential of targeting this ER? signaling axis to boost currentcancer immunotherapies. Findings from these experiments will shed light on a previously under-appreciatedsignaling pathway governing tumor-immune cell interactions in the tumor microenvironment. Asimmunotherapies are becoming an important pillar of cancer therapy, the proposed study will help improveclinical outcomes and efficacy of immunotherapy for larger numbers of cancer patients.