权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Regulation of the tumor microenvironment by DNA damage repair proteins

DNA损伤修复蛋白调节肿瘤微环境

基本信息

批准号：
10737565
负责人：
Svasti Haricharan
金额：
$ 31.31万
依托单位：
SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-07-14 至 2024-01-15
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10737565
关键词：
Affect Antibodies Breast Cancer Cell Cell Communication Cell Culture Techniques Cells Clinical Cytosol DNA DNA Repair DNA Sequence Alteration Data Dependence Diagnosis Dimerization ERBB2 gene ErbB4 gene Estrogen receptor positive Experimental Models FDA approved Family member Genome Stability Goals Growth Heterodimerization Impairment In Situ In Vitro Inflammatory Ligand Binding Ligand Binding Domain Ligands Link MLH1 gene Malignant Neoplasms Mammary Neoplasms Mediating Metastatic breast cancer Mismatch Repair Mutagenesis Mutate Mutation Neuregulin 1 Pathway interactions Patients Pattern Phenotype Predictive Value Predisposition Proteins Publishing RNA Interference Receptor Protein-Tyrosine Kinases Regulation Research Resistance Role Seminal Signal Transduction Stimulator of Interferon Genes Testing Therapeutic Tumor Suppressor Proteins Woman Work behavior influence betacellulin cancer cell cancer diagnosis carcinogenesis cytokine digital heparin-binding EGF-like growth factor hormone therapy in vivo inhibitor insight interest malignant breast neoplasm neoplastic cell novel novel therapeutic intervention overexpression predicting response prognostic value resistance mechanism therapy resistant treatment response tumor tumor behavior tumor growth tumor microenvironment

项目摘要

PROJECT SUMMARY Background ER+ breast cancer accounts for 2/3 of invasive breast cancer cases diagnosed in the world today. In patients, ~12% of ER+ tumors have complete loss of MLH1, a tumor suppressor and mismatch repair protein. We previously showed that MLH1 loss in ER+ breast cancer cells activates HER2 to induce resistance to standard endocrine therapy. However, the underlying mechanism remains unknown. Preliminary data support a role for MLH1 loss in altering secretion of HER ligands to mediate HER2 activation. This is of particular interest because an additional 14% of ER+ patient tumors have heterogeneous loss of MLH1. Although the functional consequence of heterogeneous MLH1 loss is as yet unknown, a role for MLH1 loss in altering the cancer secretome suggests a potentially significant impact on bulk tumor phenotypes. Hypothesis Based on our published work and preliminary data, the proposed study will test the hypothesis that MLH1 loss in ER+ breast cancer induces secretion of HER ligands, by co-opting cGAS-STING signaling, to promote HER2-dependent growth of both MLH1– and MLH1+ cells in heterogeneously MLH1– tumors. Specific Aims Aim 1 will test whether the secretion of HER ligands induced by MLH1 loss mediates HER2 activation to promote endocrine therapy resistance. Here, we will use both in vitro and in vivo approaches to determine whether the ligands secreted by MLH1- ER+ breast cancer cells promote HER2 heterodimerization and consequent activation, and thereby endocrine therapy resistant growth. Aim 2 will investigate the mechanism linking MLH1 loss to HER ligand secretion. Specifically, we will test whether inefficient DNA damage repair in the absence of MLH1 triggers the cGAS-STING secretory pathway. We will also determine how cGAS-STING activation promotes HER ligand secretion. Aim 3 will examine the therapeutic impact of heterogeneous MLH1 loss. Using in vitro and in vivo experimental models established in my lab, we will test whether HER2 activation in both MLH1+ and MLH1- cells in tumors with heterogeneous MLH1 loss renders these tumors globally susceptible to HER2 inhibitors. We will also use digital spatial profiling to assess the contribution of the secretome to signaling patterns and therapeutic response in heterogeneously MLH1- tumors. Impact The results of this study will present new therapeutic strategies to help >25,000 women diagnosed each year with ER+ breast cancer characterized by heterogeneous MLH1 loss. Our work will also provide novel insight into how MLH1 loss modulates the cGAS-STING pathway to promote a pro-growth tumor secretome. Overall, results from this study will shed new insight into the how MLH1 loss promotes cancer phenotypes.

项目总结