Investigating the role of Eya3 in the regulation of innate immune signaling cascades in Triple Negative Breast Cancer

研究 Eya3 在三阴性乳腺癌先天免疫信号级联调节中的作用

• 批准号: 10415832
• 负责人: Connor J Hughes
• 金额: $ 3.57万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-13 至 2024-01-12
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10415832
• 关键词: Apoptosis; Binding; Biology; Breast Cancer Cell; Breast Cancer Patient; CD8-Positive T-Lymphocytes; CRISPR/Cas technology; Cell physiology; Cells; Complex; Cytokine Signaling; Data; Development; Disease; Distant; Distant Metastasis; ERBB2 gene; Embryonic Development; Estrogen Receptors; Eye; Family; Family member; Genetic; Genetic Transcription; Growth; Growth Factor Receptors; Homeodomain Proteins; Human; Immune; Immune Evasion; Immune signaling; Immunocompetent; Immunosuppression; Immunotherapy; In Vitro; Infiltration; Innate Immune Response; Laboratories; Lead; Malignant Neoplasms; Mediating; Mentors; Mind; Mus; NF-kappa B; Neoplasm Metastasis; Pathway interactions; Pharmacology; Phenotype; Phosphoric Monoester Hydrolases; Phosphorylation; Play; Point Mutation; Population; Prevention; Primary Neoplasm; Process; Prognosis; Protein Family; Protein Phosphatase 2A Regulatory Subunit PR53; Protein Serine/Threonine Phosphatase; Protein Tyrosine Phosphatase; Protein phosphatase; Proteins; Publishing; Regulation; Resistance; Role; Signal Pathway; Signal Transduction; Testing; Threonine; Tyrosine; Work; adaptive immune response; angiogenesis; breast cancer progression; chemokine; cofactor; cytokine; experimental study; immunoregulation; improved; in vivo; insight; knock-down; malignant breast neoplasm; migration; mouse model; neoplastic cell; new therapeutic target; novel; novel therapeutic intervention; overexpression; phosphoproteomics; prevent; programmed cell death ligand 1; small hairpin RNA; targeted treatment; therapeutic development; therapeutic target; triple-negative invasive breast carcinoma; tumor; tumor growth; tumor microenvironment; tumor progression

PROJECT SUMMARY/ABSTRACT: Triple Negative Breast Cancer (TNBC) is a subtype of breast cancer characterized by low or absent expression of the estrogen receptor and the HER2 growth factor receptor. TNBC has high rates of metastasis and an overall poor prognosis in large part due to a lack of targeted therapeutics for treating both localized and disseminated disease. The Eyes absent (Eya) family of proteins are transcriptional cofactors that possess both intrinsic tyrosine phosphatase and associated serine/threonine phosphatase activity, and this family of proteins has been shown to play important roles in normal development in mice and humans. In addition to their developmental roles, Eya proteins have also been implicated in promoting nearly all known hallmarks of cancer. Recent published work from the laboratory of my mentor, Dr. Heide Ford, demonstrated that Eya3 plays an important role in suppressing CD8+ T-cell function within TNBC tumors by downregulating expression of PD-L1, primarily through its threonine phosphatase activity, and preliminary data suggests that it may also play a role in regulating the expression of various cytokines/chemokines in this context. Activation of innate immune signaling cascades in tumor cells, such as NF-kB, and downstream cytokine/chemokine signaling, has been shown to promote tumor progression, immune evasion, and distant metastasis in a variety of tumor types, including breast cancer. In preliminary experiments, we observed that shRNA-mediated Eya3 knockdown (KD) in murine TNBC cells reduced expression of multiple cytokines and chemokines and reduced NF-kB activation in vitro, suggesting a strong regulatory role of Eya3 in these signaling cascades. Additionally, in vivo experiments suggest that Eya3 KD in murine TNBC cells greatly reduces primary tumor growth and spontaneous metastasis in immune-competent mouse models, and this change correlates with significant alterations in innate immune populations within the Eya3 KD tumors compared to their control counterparts. With these preliminary findings in mind, we hypothesize that Eya3 expression regulates an innate immune signaling axis in TNBC cells which alters chemokine/cytokine signaling in the tumor microenvironment and facilitates enhanced primary tumor growth and metastasis. Our aims are as follows: 1. To determine the contribution of Eya3-mediated induction of innate immune signaling in TNBC cells to tumor-initiated immune suppression, tumor growth, and metastasis and 2. To identify the mechanism of action by which Eya3 regulates innate immune signaling pathways in TNBC. These studies present an opportunity not only to investigate the important biology governing tumor cell crosstalk and mechanisms of immune subversion, but additionally will identify potential novel therapeutic targets for prevention or treatment of disseminated TNBC.

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