BRCA1 regulation of breast cancer cell motility
<p>Breast cancer remains a leading cause of cancer-related mortality globally, generating a need for a deeper understanding of the molecular mechanisms driving its progression. The protein product of BRCA1, a crucial tumour suppressor gene, has emerged as a pivotal player in various cellular p...
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| Format: | Thesis |
| Language: | English |
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2023
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| _version_ | 1824458924964708352 |
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| author | Hernandez Nuñez, ZE |
| author2 | Sengupta, S |
| author_facet | Sengupta, S Hernandez Nuñez, ZE |
| author_sort | Hernandez Nuñez, ZE |
| collection | OXFORD |
| description | <p>Breast cancer remains a leading cause of cancer-related mortality globally, generating a need for a deeper understanding of the molecular mechanisms driving its progression. The protein product of BRCA1, a crucial tumour suppressor gene, has emerged as a pivotal player in various cellular processes, including control of cell migration by its ubiquitin ligase activity. Mutations in BRCA1 have been implicated in the increased risk of developing several cancers. This thesis hypothesises the potential association between BRCA1 ubiquitin ligase activity and cell migration. Different databases were compiled to 1) identify substrates of BRCA1’s enzymatic activity, 2) find proteins that interact with BRCA1 and 3) find proteins with a role in regulating migration. Candidate proteins were identified as the intersection of these three categories. To validate these candidates in vitro cell culture models were developed. Time-lapse microscopy of breast cancer cell lines with various BRCA1 backgrounds was employed to evaluate the impact of inhibiting ubiquitin ligase activity. BRCA1 ubiquitin ligase activity was inhibited using three distinct approaches: 1) overexpression of a point mutation in the BRCA1 gene, 2) pharmacological inhibition with cisplatin, and 3) inducible BRCA1 degradation.</p>
<p>The results revealed that inhibition of ubiquitin ligase activity led to increased motility across all three models. These models were used in conjunction with the siRNA knockdown of candidate proteins from the <em>in-silico</em> analysis. siRNA knockdown of SART3 significantly enhanced motility in cells lacking BRCA’s ubiquitin ligase activity, highlighting its potential role in promoting cell motility and emphasising the regulatory role of BRCA1’s ubiquitin ligase activity in breast cancer progression.</p>
<p>These findings underscore the therapeutic potential of targeting BRCA1-associated pathways, particularly SART3, in breast cancer treatment. Future investigations could explore diagnostic and therapies targeting BRCA1 enzymatic activity and SART3 pathways implicated in breast cancer pathogenesis.</p> |
| first_indexed | 2025-02-19T04:33:38Z |
| format | Thesis |
| id | oxford-uuid:ba4973c0-0e19-4c9b-92f4-5733455dac0d |
| institution | University of Oxford |
| language | English |
| last_indexed | 2025-02-19T04:33:38Z |
| publishDate | 2023 |
| record_format | dspace |
| spelling | oxford-uuid:ba4973c0-0e19-4c9b-92f4-5733455dac0d2025-01-21T08:30:13ZBRCA1 regulation of breast cancer cell motilityThesishttp://purl.org/coar/resource_type/c_db06uuid:ba4973c0-0e19-4c9b-92f4-5733455dac0dBRCA genesEnglishHyrax Deposit2023Hernandez Nuñez, ZESengupta, SVaux, D<p>Breast cancer remains a leading cause of cancer-related mortality globally, generating a need for a deeper understanding of the molecular mechanisms driving its progression. The protein product of BRCA1, a crucial tumour suppressor gene, has emerged as a pivotal player in various cellular processes, including control of cell migration by its ubiquitin ligase activity. Mutations in BRCA1 have been implicated in the increased risk of developing several cancers. This thesis hypothesises the potential association between BRCA1 ubiquitin ligase activity and cell migration. Different databases were compiled to 1) identify substrates of BRCA1’s enzymatic activity, 2) find proteins that interact with BRCA1 and 3) find proteins with a role in regulating migration. Candidate proteins were identified as the intersection of these three categories. To validate these candidates in vitro cell culture models were developed. Time-lapse microscopy of breast cancer cell lines with various BRCA1 backgrounds was employed to evaluate the impact of inhibiting ubiquitin ligase activity. BRCA1 ubiquitin ligase activity was inhibited using three distinct approaches: 1) overexpression of a point mutation in the BRCA1 gene, 2) pharmacological inhibition with cisplatin, and 3) inducible BRCA1 degradation.</p> <p>The results revealed that inhibition of ubiquitin ligase activity led to increased motility across all three models. These models were used in conjunction with the siRNA knockdown of candidate proteins from the <em>in-silico</em> analysis. siRNA knockdown of SART3 significantly enhanced motility in cells lacking BRCA’s ubiquitin ligase activity, highlighting its potential role in promoting cell motility and emphasising the regulatory role of BRCA1’s ubiquitin ligase activity in breast cancer progression.</p> <p>These findings underscore the therapeutic potential of targeting BRCA1-associated pathways, particularly SART3, in breast cancer treatment. Future investigations could explore diagnostic and therapies targeting BRCA1 enzymatic activity and SART3 pathways implicated in breast cancer pathogenesis.</p> |
| spellingShingle | BRCA genes Hernandez Nuñez, ZE BRCA1 regulation of breast cancer cell motility |
| title | BRCA1 regulation of breast cancer cell motility |
| title_full | BRCA1 regulation of breast cancer cell motility |
| title_fullStr | BRCA1 regulation of breast cancer cell motility |
| title_full_unstemmed | BRCA1 regulation of breast cancer cell motility |
| title_short | BRCA1 regulation of breast cancer cell motility |
| title_sort | brca1 regulation of breast cancer cell motility |
| topic | BRCA genes |
| work_keys_str_mv | AT hernandeznunezze brca1regulationofbreastcancercellmotility |