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• W2737389365 abstract "Breast cancer is one of top three diagnosed cancers in Australia and other countries. Approximately 64% of human breast cancers are oestrogen receptor positive (ER+) and express the MYB oncogene. The MYB oncogene encodes a transcription factor (MYB) that regulates many cellular genes such as genes that are associated with cell proliferation, differentiation and apoptosis. To date, most MYB target genes have been identified and characterized in hematopoietic cells; MYB and its target genes are still understudied in human ER+ breast cancer cells. Previous studies from our laboratory found that MYB expression is necessary for proliferation of human ER+ breast cancer cells and for tumour development in vivo. Furthermore, overexpression of MYB prevented chemically-induced differentiation of human ER+ breast cancer. Moreover, shRNA-mediated MYB knockdown initiated differentiation of human ER+ breast cancer cells, and greatly sensitised them to chemically-induced apoptosis. There were three main aims of this thesis that focused on identification of MYB target genes, the function of MYB in DNA damage response and the role of MYB in breast cancer stem cells. The first aim of this thesis was to identify and validate MYB target genes in human ER+ breast cancer cells by using doxycycline (Dox)-inducible MYB shRNA to knockdown MYB and using RNA-Seq gene expression profiling. Chapter 3 of this thesis showed cells expressing MYB shRNA showed 80% MYB knockdown and 40% inhibition of cell proliferation, compared to nonsilencing control. These cells were used to identify MYB target genes using RNA-Seq gene expression profiling. Approximately 500 genes showed differential expression between two MYB shRNA groups, compared to nonsilencing control. After integration with published chromatin immunoprecipitation data, 145 potentially direct MYB target genes including several DNA damage response genes were identified. There is very little information on the role of MYB in the DNA damage response of ER+ breast cancer cells. However, two studies showed that silencing MYB increased radiation-induced DNA damage in nasopharyngeal carcinoma and DNA damage-induced cell death in castration resistant prostate cancer cells. Therefore, the second aim of this thesis was to investigate the role of MYB and its target genes in DNA damage responses in human ER+ breast cancer cells. Chapter 5 of this thesis showed that MYB knock down sensitized ER+ breast cancer cells to DNA damaging reagents. This may result from downregulation of BCL2, increasing DNA damage, an effect on DNA damage response such as RAD51 foci formation or a combination of effects. From RNA-Seq results, there was a cancer stem cell-related gene (ALDH1A3) that was identified as a potentially direct MYB target gene. A previous study showed that a cancer stem cell-related gene (NANOG) was identified as a MYB target genes in human ER+ breast cancer MCF-7 cells. The cancer stem cell theory proposes that tumours may arise from a small population of cancer cells with stem cell properties. Mammosphere culture is an in vitro surrogate assay to culture cancer stem cells in an undifferentiated state and to examine cancer stem cell properties such as self-renew. Although MYB has been studied in breast cancer in vitro and tumour formation in vivo, there is very little information on the roles of MYB in ER+ breast cancer stem cells. Therefore, the third aim of this thesis was to examine the potential role of MYB in human ER+ breast cancer stem cells. Chapter 6 of this thesis showed that MYB expression was increased during serial passage of mammosphere-derived cells, compared to the first generation. However, silencing MYB may not affect mammosphere-forming ability of MCF-7 cells. This thesis makes contributions of significance as follows: (1) further understanding of how MYB and its target genes contribute to control cell proliferation and DNA damage response in human ER+ breast cancer; (2) these genes may be potential targets for the development of specific therapeutics; (3) understanding the role of MYB in cancer stem cells derived from human ER+ breast cancer." @default.
• W2737389365 created "2017-07-31" @default.
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• W2737389365 date "2016-12-12" @default.
• W2737389365 modified "2023-09-27" @default.
• W2737389365 title "Understanding the role of the MYB oncogene in human breast cancer: targets and functions" @default.
• W2737389365 doi "https://doi.org/10.14264/uql.2016.1135" @default.
• W2737389365 hasPublicationYear "2016" @default.
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