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Understanding the role of BRCA1 in redox homeostasis regulation
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Zwyea, Susan. Understanding the role of BRCA1 in redox homeostasis regulation. Retrieved from https://doi.org/doi:10.7282/T3F76GRG

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TitleUnderstanding the role of BRCA1 in redox homeostasis regulation
NameZwyea, Susan (author); Walworth, Nancy (chair); Rutgers University; School of Graduate Studies
Date Created2017
Other Date2017-10 (degree)
SubjectMicrobiology and Molecular Genetics, BRCA genes, Breast--Cancer
Extent1 online resource (xiii, 106 p. : ill.)
DescriptionThe BRCA1 (Breast Cancer 1, early onset) tumor suppressor gene is the most frequently mutated gene in familial breast cancer. Loss of BRCA1 function results in severe defects in DNA double-strand break repair and increased reactive oxygen species, both of which are threats to genomic stability. Although BRCA1 has been extensively studied, how it regulates redox homeostasis remains poorly understood and need to be further elucidated. Of note, a recent study suggested that BRCA1 promotes the transcription of SOD2/MnSOD, the mitochondrial superoxide dismutase. In this study, we found that BRCA1 depletion showed limited effect on SOD2 mRNA levels in multiple settings. Instead, we found an inverse between BRCA1 and SOD2 protein abundance, as breast cancer cells depleted of BRCA1 show increased SOD2 protein levels. In addition, deletion of Brca1 in mice led to increased SOD2 amount in the liver. Our studies suggest that BRCA1 may be involved in the regulation of SOD2 protein stability and/or that SOD2 is stabilized in response to the oxidative stress induced by BRCA1 loss. Our gene expression analysis of human breast cancers showed that triple negative breast cancers have the highest SOD2 mRNA levels among all subtypes. Interestingly, low SOD2 mRNA level is associated with slightly better prognosis in all patients but substantially worse survival in patients with triple negative or HER2-positive tumors. This finding suggests that SOD2 may modulate sensitivity of breast cancer cells to chemotherapies. Indeed, triple negative breast cancer cell lines depleted of SOD2 show resistance to breast cancer chemotherapies. Taken together, our studies identify a novel mechanism of BRCA1 in regulating redox homeostasis and a novel role of SOD2 in modulating therapy response.
NotePh.D.
NoteIncludes bibliographical references
Noteby Susan Zwyea
Genretheses, ETD doctoral
Persistent URLhttps://doi.org/doi:10.7282/T3F76GRG
Languageeng
CollectionSchool of Graduate Studies Electronic Theses and Dissertations
Organization NameRutgers, The State University of New Jersey
RightsThe author owns the copyright to this work.
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