MnSOD Acetylation Promotes Cancer Stem Cell Phenotypes in Breast Cancer

MnSOD 乙酰化促进乳腺癌干细胞表型

• 批准号: 9763487
• 负责人: Marcelo G Bonini
• 金额: $ 34.17万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-14 至 2020-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9763487
• 关键词: Abbreviations; Acetylation; Advisory Committees; Aging; Antioxidants; Behavior; Biochemical; Biochemical Process; Biological Markers; Breast; Breast Cancer Cell; Breast Cancer Patient; Cancer Patient; Cells; Characteristics; Chemicals; Chicago; Clinical; Collection; Development; Diffuse; Disease; Doxorubicin; Drug resistance; Enzymes; Estrogen Receptors; Exhibits; Genetic; Hand; Hydrogen Peroxide; Hypoxia; Laboratories; Lead; Link; Lysine; Malignant Neoplasms; Mammary Neoplasms; Mediating; Metabolic; Metabolic stress; Metastatic breast cancer; Mitochondria; Molecular; Molecular Profiling; Molecular Target; Mouse Mammary Tumor Virus; Mus; Neoplasm Metastasis; Normal tissue morphology; Oncoproteins; Oxidative Stress; Paclitaxel; Patients; Peroxidases; Pharmacotherapy; Phenotype; Post-Translational Protein Processing; Primary Neoplasm; Production; Reactive Oxygen Species; Records; Recurrence; Reporting; Research; Resistance; Resistance development; Risk; Role; SOD2 gene; Sampling; Signal Transduction; Stem cells; Structure; Testing; Transgenes; Translating; Treatment Failure; Tumor Suppressor Proteins; Urban Hospitals; Woman; base; cancer stem cell; cancer subtypes; catalase; cohort; conventional therapy; epidemiology study; ethnic diversity; follow-up; gain of function; malignant breast neoplasm; malignant phenotype; mitochondrial metabolism; monomer; mouse model; mutant; neoplastic cell; new therapeutic target; novel; prevent; response; restoration; standard of care; stem; stem-like cell; stemness; therapeutic target; tumor; tumor initiation; tumor progression

PROJECT SUMMARY / ABSTRACT: Cancer stem cells are a rare and yet critically important subpopulation of cells in tumors associated with treatment failure and metastatic recurrence. Though it is becoming increasingly clear that targeting this subpopulation could lead to therapies with better odds of a cure it is still unknown how these cells originate and what are the biochemical processes that promote “stemness” in cancer. Our laboratory found that alterations in the metabolism of mitochondrial reactive oxygen species (ROS) promote aberrant activation of hypoxia-induced factor 2α (HIF2α). The activation of HIF2α is a well-established mechanism of stemness that has also been implicated in metastatic recurrence as well as treatment failure in women with breast cancer. We found that a posttranslational modification (i.e. acetylation) of a primary enzyme involved in the metabolism of mitochondrial ROS, manganese superoxide dismutase (MnSOD) breaks the tetrameric structure that has antioxidant function turning the enzyme into a monomer that promotes ROS formation and activates HIF2α. We also found that MnSOD-K68Ac accumulates prominently in breast cancers expressing low estrogen receptor levels. Hence, it is proposed that MnSOD has a dichotomous behavior functioning as a suppressor of tumor initiation (antioxidant function) and yet promotes cancer stem cell reprogramming later on in established tumors. This proposition is supported by the finding of strong associations between a MnSOD/HIF2α signature present in metastatic lesions compared to primary tumor samples from the same breast cancer patients. Hence, this application aims at determining: (1) if MnSOD-Ac reprograms tumor cells to stem-like phenotypes associated with chemoresistance. (2) if the biochemical and/or genetic targeting of MnSOD-Ac or HIF2α in established tumors of mice with the MnSODhigh/HIF2α signature (MMTV.PyVT) suppresses chemoresistance and/or metastasis. (3) if there is an association between subsets of women with breast cancer that exhibit a MnSODhigh or MnSOD-Ac, or MnSOD-ROS-HIF2α molecular axis signature and develop chemoresistance or have increased risk of metastatic recurrence.

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