Thursday, April 3, 2025
4/3/2025
Role of the CTLH E3 ubiquitin ligase in breast cancer progression - Project Summary / Abstract HER2-positive breast cancers are highly aggressive and associated with poor prognosis. HER2-targeted therapy is the preferred treatment for these cancers, but drug resistance is a major problem. Our previous studies demonstrated that dysregulation of G protein coupled receptors, in particular, a subgroup of GPCRs that couple to G protein αi/o subunits (Gi/o-GPCRs), contributes to HER2-induced breast cancer initiation and progression. Targeting Gi/o-GPCR signaling blocks tumor progression and enhances the efficacy of HER2-targeted therapy. This proposal aims to delineate how dysregulated Gi/o-GPCR signaling may control HER2+ breast cancer progression through a poorly studied CTLH E3 ubiquitin ligase complex. The CTLH (carboxy-terminal to LisH domain) complex is a mammalian ortholog of the yeast GID (glucose-induced-degradation-deficient) complex that contains multiple subunits, including an adaptor/scaffold protein, WDR26, which may be required for CTLH complex assembly and recruitment of specific substrates for ubiquitination and degradation. The CTLH complex was implicated in tumorigenesis but its exact functions in tumor development remain largely unknown. We previously found WDR26 is a scaffolding protein that regulates GPCR signaling and is highly upregulated in all molecular subtypes of invasive breast carcinoma and associated with worse prognosis. In preliminary studies, we tested WDR26 gene deletion in a Neu transgenic mouse model of HER2+ breast cancer and showed mammary-specific WDR26 gene deletion recapitulated a Gi/o-GPCR-signaling blockade: both inhibited tumor initiation, growth, and lung metastasis. WDR26 likely promotes both G protein signaling and controls CTLH- ubiquitin-ligase-driven degradation of SNF5 (an epigenetic tumor suppressor) in tumor cells. Based on these exciting preliminary data, we hypothesize that, in HER2-driven breast tumors, WDR26 upregulation promotes G-protein signaling and facilitates nuclear CTLH-complex assembly and E3 ubiquitin ligase activity, leading to ubiquitination and proteasomal degradation of SNF5; and this SNF5 depletion activates oncogenic transcriptional programs, in part, by upregulating EZH2 (enhancer of zeste homology 2), ultimately promoting tumor growth and metastasis and resistance to HER2-targeted therapy. In this study, using a combination of cell lines, several newly developed genetic and patient-derived xenograft mouse models, we will determine 1) how WDR26 manifests dysregulated Gi/o-GPCR signaling to drive breast cancer progression via the CTLH complex; 2) how the CTLH complex regulates breast cancer development by targeting SNF5 for proteasomal degradation; and 3) whether targeting the CTLH and SNF5 function improves the efficacy of HER2-targeted therapy. The results of our studies should fundamentally advance understanding of how the poorly studied CTLH E3 ubiquitin ligase complex targets the epigenetic tumor suppressor SNF5 to drive tumor progression and drug resistance. This knowledge should help us identify new strategies for augmenting HER2-targeted therapy in breast cancer.
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