Research Projects

Cancer Treatment Research – Dr Sharon Prince

Cancer Treatment Research – Dr Sharon Prince

Dr Sharon Prince

Title of the project

Identification of novel therapeutic strategies to treat cancer by targeting the cell cycle regulators,TBX2 AND TBX3

Project description

Cancer formation results from cells acquiring the ability to divide in an uncontrolled fashion. Cell division is carefully regulated by proteins responsible for either triggering or for preventing a cell from dividing. If this balance is disrupted then the end result can be cell death or cancer. Two closely related proteins, or transcription factors, TBX2 and TBX3, are examples of proteins which regulate the gene expression (production of other proteins) involved in cell division and play a pivotal role during embryonic development. These proteins have previously also been implicated in the formation of cancer. Whereas TBX2 and TBX3 generally exist at low levels in adult tissue they are often present at abnormally high levels in a number of cancers including breast, pancreatic, melanoma, liver and bladder. Our laboratory has convincingly shown by reducing TBX2 or TBX3 levels in breast cancer and melanoma cell lines, which produce high levels of these proteins, that they both play important, but distinct roles in cancer formation (Peres et al, 2010). Whereas TBX2 was required for elevated cell proliferation, TBX3 was required for cell migration and the spreading of cancer to other organs, a process called metastasis. We therefore believe that the abnormally high levels of TBX2 and TBX3 in these cancers cause the cells to divide inappropriately and that drugs which reduce the levels of these proteins will be hugely beneficial for the treatment of many cancers. While we have made significant progress towards identifying some of the pathways that regulate TBX2 and TBX3 gene expression, this project aims to identify proteins that bind to and help (co-factors) TBX2 and TBX3 in their activity to make cells cancerous. We also plan to identify downstream TBX2 and TBX3 target genes which are responsible for mediating their roles in cancer.

Non-scientific report:

As described earlier, this project aims to identify co-factors that bind to and help TBX2 and TBX3 in their activity to make cells cancerous. We also wish to identify downstream TBX2 and TBX3 target genes which are responsible for mediating their roles in cancer.
To address these aims, we are using two main strategies: the first is to perform high throughput screens to identify new TBX2 and TBX3 target genes and co-factors from an array of genes or proteins respectively. The second is to test the regulation or interaction of TBX2/3 with specific genes or proteins, respectively that we have identified as likely candidates. To date we have identified a number of new proteins that interact with TBX2/TBX3 and have chosen to explore the significance of the interaction of two particular proteins, viz p53 and c-MYB, which play critical roles in cancer. This investigation has also led to the discovery of a number of TBX2/3 target genes which provides insight into how they may help cells to proliferate uncontrollably and evade barriers to cancer such as senescence and programmed cell death. Furthermore, we have discovered that TBX3 represses a number of genes involved in a process that allows cells to adhere together to form tissues, which likely explains how TBX3 is able to promote cell migration and metastasis. By identifying these target genes and interacting factors we are providing key insight into the complex role that TBX2/TBX3 play in cancer development and we are revealing more versatile targets to treat cancers caused by these two factors.

Abstracts

Conferences

  • Jade Peres, Wendy Kröger, Shaheen Mowla and Sharon Prince (2010) The Role of the T-box transcription Factor TBX3 in Melanoma Progression. Cancer Research UK Beatson International Cancer Conference, Scotland, UK.

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