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TAZ (Transcriptional co-activator with PDZ-binding motif) is a WW-domain containing protein recently identified as a downstream component of the Hippo tumor suppressor pathway and mediator of biologically important processes (mesenchymal stem cell differentiation, embryonic stem cell renewal, mechanotransduction). Recently, loss of LATS1/2, a negative regulator of TAZ, has been observed in ~50% of breast cancers. However, whether and how TAZ is also involved in breast cancer has not been investigated. Therefore, this study explores the cellular functions of TAZ in breast cancer and the underlying molecular mechanisms. The cellular functions of TAZ were investigated using overexpression studies in an immortalized mammary epithelial cell line (MCF10A). Compared to control vector-only expressing cells (MCF10A-WPI) TAZ overexpression (MCF10A-TAZ) promotes enhanced cell proliferation, cell migration and cell-ECM adhesion, induces transformation and the epithelial-mesenchymal transition, and confers resistance to chemotherapeutics (paclitaxel, cisplatin). Together, these findings strongly suggest TAZ functions as an oncogene in the development, progression and drug resistance of breast cancer. As a transcriptional co-activator, TAZ likely mediates these cellular functions through the transcriptional activation of downstream genes. By screening a 44K human genome microarray we have identified and characterized Cyr61 and CTGF, mediators of paclitaxel resistance, and BMP4, a regulator of cell migration. Through stable shRNA-mediated knockdown, we show that loss of Cyr61/CTGF expression in MCF10A-TAZ cells can rescue TAZ-induced paclitaxel resistance. Similarly, shRNA-mediated knockdown of BMP4 can significantly attenuate TAZ-induced cell migration. Therefore, these findings demonstrate that Cyr61/CTGF and BMP4 are functionally significant mediators of TAZ-induced paclitaxel resistance and cell migration, respectively. The clinical relevance of our in vitro findings were also validated by immunohistochemistry using tissue microarrays containing human breast cancer samples. TAZ levels were highly expressed in 66.6% of clinical samples further suggesting TAZ may be an important oncogene in breast cancer. Our study has characterized TAZ as an oncogene in breast cancer and elucidated two novel mechanisms underlying paclitaxel resistance and cell migration. These findings highlight the importance of TAZ during the development, progression and drug resistance of breast cancers and the potential use of TAZ as a therapeutic target to treat TAZ-expressing breast cancers. / Thesis (Ph.D, Pathology & Molecular Medicine) -- Queen's University, 2013-08-01 23:59:08.68

>Magister Scientiae - MSc / Retinoblastoma Binding Protein 6 (RBBP6) is a 200 KDa multi-domain protein that has been shown to play a role in mRNA processing, cell cycle arrest and apoptosis. RBBP6 interacts with tumour suppressor proteins such as p53 and pRb and has been shown cooperate with Murine Double Minute 2 (MDM2) protein in catalyzing ubiquitination and suppression of p53. Unpublished data from our laboratory has suggested that RBBP6 and MDM2 interact with each other through their RING finger domains. RBBP6 has also been shown to have its own E3 ubiquitin ligase activity, catalyzing ubiquitination of Y-Box Binding Protein 1 (YB-1) in vitro and in vivo. YB- 1 is a multifunctional oncogenic protein that is generally associated with poor prognosis in cancer, tumourigenesis, metastasis and chemotherapeutic resistance. Unpublished data from our laboratory shows that RBBP6 catalyzes poly-ubiquitination of YB-1, using Ubiquitin-conjugating enzyme H1 (UbcH1) as E2 ubiquitin conjugating enzyme. / 2022-02-25

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京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第21447号 / 医博第4414号 / 新制||医||1032(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 武藤 学, 教授 平井 豊博, 教授 岩田 想 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM