Identification and characterization of transcriptional targets of TAZ in human breast cancer
van Rensburg, Ellen
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TAZ is a transcriptional co-activator and an effector of the Hippo signaling pathway. Since its discovery in 2000, we have gained tremendous insights into the roles TAZ plays in development and disease. TAZ acts as an oncogene in human breast cancers. Mechanistic studies have demonstrated that TAZ directs multiple aspects of breast cancer cell behaviour (e.g. cell proliferation, cell migration/invasion, stem cell phenotypes, chemotherapy resistance). While these processes represent critical cancer cell-intrinsic functions for TAZ, little is known about how breast cancer cell TAZ expression affects the ways that cancer cells respond to, or manipulate, factors in their tumour microenvironment (e.g. growth factors, non-neoplastic cells). Over the past decade, our lab has aimed to understand the precise gene targets transcriptionally regulated by TAZ that mediate its activities in breast cancer. In my thesis, I explore how TAZ influences breast cancer cell behaviour in response to extrinsic factors and identify specific gene targets of TAZ that mediate these interactions. First, I show that TAZ directly regulates the expression of a key component in the insulin signaling pathway, IRS1. Upregulation of IRS1 by TAZ contributes to TAZ-induced proliferation of mammary epithelial cells in 3D culture in the presence or absence of supplemental insulin. I next explore whether cancer cell TAZ expression can modify the anti-neoplastic immune response. I use NanoString to specifically screen for immune-related transcriptional targets of TAZ and discover that TAZ affects the mRNA expression of many gene targets that are relevant to immunology. I identify the immune checkpoint molecule, PD-L1 as a TAZ-regulated gene. Upregulation of PD-L1 by TAZ impairs T cell function in co-culture experiments. Interestingly, I uncover evidence that PD-L1 is not upregulated by TAZ in multiple mouse cell lines suggesting that this relationship may not be conserved across species. Through this work, I have uncovered two distinct mechanisms by which TAZ affects interactions between breast cancer cells and their environment. These findings provide insights into the roles of TAZ in neoplastic and non-neoplastic disease processes and may provide the foundation for future studies investigating novel strategies for targeting TAZ-high breast cancers.