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postgraduate thesis: The regulation of oxidative stress in the development of drug resistance in the treatment of breast cancer
Title | The regulation of oxidative stress in the development of drug resistance in the treatment of breast cancer |
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Authors | |
Advisors | Advisor(s):Khoo, US |
Issue Date | 2018 |
Publisher | The University of Hong Kong (Pokfulam, Hong Kong) |
Citation | Leung, M. [梁文康]. (2018). The regulation of oxidative stress in the development of drug resistance in the treatment of breast cancer. (Thesis). University of Hong Kong, Pokfulam, Hong Kong SAR. |
Abstract | Breast cancer is the most common type of female cancer. Reactive oxygen species (ROS) plays an important role in regulating signaling pathways that control cell survival and cell proliferation. Oxidative stress refers to the imbalance between ROS generation and ROS elimination. A number of chemotherapeutic drugs, such as taxanes, platinum compounds and anthracyclines trigger cell death via induction of oxidative stress. Development of drug resistance in cancer is associated with the adaptive response to oxidative stress. NRF2 is the main regulator of cytoprotective response to oxidative stress. Increased activity of NRF2 enhances cell growth and increases chemoresistance, providing growth advantage for malignant cells.
My study aims to identify molecular mechanisms that are involved in the development of drug resistance via modulation of oxidative stress in breast cancer. The novel molecular mechanisms through which NRF2 activity would be enhanced to confer drug resistance in breast cancer cells are explained.
FOXM1 is a well-known oncogene which contributes to all hallmarks of cancer. In Chapter 3, we hypothesized that FOXM1 and NRF2 are involved together in contributing to chemoresistance via modulation of oxidative stress. We showed that chemoresistant breast cancer cells express higher levels of FOXM1 and NRF2. These resistant cells have higher resistance to oxidative stress-mediated cell death and to ROS induction by tBHP. In drug sensitive MCF-7, we found that FOXM1 regulates NRF2 and NRF2 target genes expression. Transcriptional activation on antioxidant response element (ARE) was mediated by FOXM1 in response to epirubicin. ChIP-qPCR result further supported that FOXM1 transcriptionally controlledNRF2 expression. However, the identified FOXM1/NRF2 axis was deregulated in chemoresistant cells. Nevertheless, the use of NRF2 inhibitor could enhance the efficacy of epirubicin treatment to treat breast cancer. Our findings showed that FOXM1 regulates the transcription of NRF2 which mediates response to epirubicin and eventual epirubicin resistance in breast cancer cells.
Our group have identified BQ323636.1 (BQ), as a novel splice variant of NCOR2 which could predict tamoxifen resistance in the treatment of breast cancer. In Chapter 4, we hypothesized that BQ could modulate oxidative stress in breast cancer. Overexpressing BQ in breast cancer cell lines could promote cell proliferation and protect cells from oxidative stress. In addition, we showed overexpression of BQ could reduce the levels of ROS. By RT-qPCR assay, several downstream NRF2 targets were found to be up-regulated in BQ overexpressing cells, suggesting that NRF2 transcriptional activity could be modulated by BQ. Luciferase reporter assay showed that NCOR2 could repress the transcriptional activity via antioxidant response element (ARE), which is the primary binding site of NRF2 in the promoter region. Furthermore, BQ could reverse the repressive effect of NCOR2 on ARE. These results suggest that BQ might modulate NRF2 activity via NCOR2. Immunoprecipitation assay indicated NCOR2 interacted with NRF2 and BQ overexpression could inhibit this interaction. Taken together, our findings suggested BQ regulates NRF2 signaling pathway via interfering with NCOR2 activity. Our findings reveal a novel role for BQ as a modulator of NRF2 and oxidative stress in breast cancer.
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Degree | Doctor of Philosophy |
Subject | Oxidative stress Drug resistance In cancer cells Breast cancer - Treatment |
Dept/Program | Pathology |
Persistent Identifier | http://hdl.handle.net/10722/271626 |
DC Field | Value | Language |
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dc.contributor.advisor | Khoo, US | - |
dc.contributor.author | Leung, Man-hong | - |
dc.contributor.author | 梁文康 | - |
dc.date.accessioned | 2019-07-10T03:19:03Z | - |
dc.date.available | 2019-07-10T03:19:03Z | - |
dc.date.issued | 2018 | - |
dc.identifier.citation | Leung, M. [梁文康]. (2018). The regulation of oxidative stress in the development of drug resistance in the treatment of breast cancer. (Thesis). University of Hong Kong, Pokfulam, Hong Kong SAR. | - |
dc.identifier.uri | http://hdl.handle.net/10722/271626 | - |
dc.description.abstract | Breast cancer is the most common type of female cancer. Reactive oxygen species (ROS) plays an important role in regulating signaling pathways that control cell survival and cell proliferation. Oxidative stress refers to the imbalance between ROS generation and ROS elimination. A number of chemotherapeutic drugs, such as taxanes, platinum compounds and anthracyclines trigger cell death via induction of oxidative stress. Development of drug resistance in cancer is associated with the adaptive response to oxidative stress. NRF2 is the main regulator of cytoprotective response to oxidative stress. Increased activity of NRF2 enhances cell growth and increases chemoresistance, providing growth advantage for malignant cells. My study aims to identify molecular mechanisms that are involved in the development of drug resistance via modulation of oxidative stress in breast cancer. The novel molecular mechanisms through which NRF2 activity would be enhanced to confer drug resistance in breast cancer cells are explained. FOXM1 is a well-known oncogene which contributes to all hallmarks of cancer. In Chapter 3, we hypothesized that FOXM1 and NRF2 are involved together in contributing to chemoresistance via modulation of oxidative stress. We showed that chemoresistant breast cancer cells express higher levels of FOXM1 and NRF2. These resistant cells have higher resistance to oxidative stress-mediated cell death and to ROS induction by tBHP. In drug sensitive MCF-7, we found that FOXM1 regulates NRF2 and NRF2 target genes expression. Transcriptional activation on antioxidant response element (ARE) was mediated by FOXM1 in response to epirubicin. ChIP-qPCR result further supported that FOXM1 transcriptionally controlledNRF2 expression. However, the identified FOXM1/NRF2 axis was deregulated in chemoresistant cells. Nevertheless, the use of NRF2 inhibitor could enhance the efficacy of epirubicin treatment to treat breast cancer. Our findings showed that FOXM1 regulates the transcription of NRF2 which mediates response to epirubicin and eventual epirubicin resistance in breast cancer cells. Our group have identified BQ323636.1 (BQ), as a novel splice variant of NCOR2 which could predict tamoxifen resistance in the treatment of breast cancer. In Chapter 4, we hypothesized that BQ could modulate oxidative stress in breast cancer. Overexpressing BQ in breast cancer cell lines could promote cell proliferation and protect cells from oxidative stress. In addition, we showed overexpression of BQ could reduce the levels of ROS. By RT-qPCR assay, several downstream NRF2 targets were found to be up-regulated in BQ overexpressing cells, suggesting that NRF2 transcriptional activity could be modulated by BQ. Luciferase reporter assay showed that NCOR2 could repress the transcriptional activity via antioxidant response element (ARE), which is the primary binding site of NRF2 in the promoter region. Furthermore, BQ could reverse the repressive effect of NCOR2 on ARE. These results suggest that BQ might modulate NRF2 activity via NCOR2. Immunoprecipitation assay indicated NCOR2 interacted with NRF2 and BQ overexpression could inhibit this interaction. Taken together, our findings suggested BQ regulates NRF2 signaling pathway via interfering with NCOR2 activity. Our findings reveal a novel role for BQ as a modulator of NRF2 and oxidative stress in breast cancer. | - |
dc.language | eng | - |
dc.publisher | The University of Hong Kong (Pokfulam, Hong Kong) | - |
dc.relation.ispartof | HKU Theses Online (HKUTO) | - |
dc.rights | The author retains all proprietary rights, (such as patent rights) and the right to use in future works. | - |
dc.rights | This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. | - |
dc.subject.lcsh | Oxidative stress | - |
dc.subject.lcsh | Drug resistance In cancer cells | - |
dc.subject.lcsh | Breast cancer - Treatment | - |
dc.title | The regulation of oxidative stress in the development of drug resistance in the treatment of breast cancer | - |
dc.type | PG_Thesis | - |
dc.description.thesisname | Doctor of Philosophy | - |
dc.description.thesislevel | Doctoral | - |
dc.description.thesisdiscipline | Pathology | - |
dc.description.nature | published_or_final_version | - |
dc.identifier.doi | 10.5353/th_991044046696503414 | - |
dc.date.hkucongregation | 2018 | - |
dc.date.hkucongregation | 2018 | - |
dc.identifier.mmsid | 991044046696503414 | - |