Dr Keith Brennan - Research interests
Dr Brennan's research centres on the role developmental signalling pathways play in the initiation of cancer. The majority of human cancers arise in epithelial tissues such as the colon, skin and breast. These organs turnover constantly, with damaged cells being removed by apoptosis and replaced by the controlled division and differentiation of stem cells. This process is regulated by a network of signalling pathways that are also responsible for the differentiation of the organs during embryogenesis. During the initial stages, most tumours closely resemble the tissue that they arise from suggesting that disruption of this developmental signalling network is the initial driving force in tumour formation. The aberrant activation of Wnt signalling in nearly all colorectal cancers provides a clear example of this, as the pathway also plays a pivotal role in regulating stem cell self renewal and differentiation during normal colonic development and turnover. Consequently a thorough understanding of the development of a tissue or organ will provide important insights into the changes in cell behaviour that lead to tumour initiation. Furthermore this is likely to lead to the development of rational and novel therapies to treat early stage cancers when the likelihood of cure is significantly greater.
In particular his group has focused on the role the Notch signalling pathway plays in human breast cancer. This pathway is essential for multiple aspects of metazoan development, and they have shown that elevated signalling through the pathway plays a significant role in the aetiology of human breast cancer. They observe an accumulation of NICD, the active form of Notch, in a wide variety of invasive breast cancer cell lines and tissue samples. Increased Notch signalling is also seen in ductal carcinoma in situ (DCIS) lesions, a pre-invasive form of breast cancer, where it predicts a significantly increased risk of recurrence (work done in collaboration with Gillian Farnie, Rob Clarke and Nigel Bundred). This also suggests that activation of the pathway is an early change in tumour progression. Furthermore his group has shown that this increase in Notch signalling plays a causal role in tumour formation, as blocking the pathway reverts the tumourigenic phenotype of breast cancer cell lines.
To understand how this increase in Notch signalling leads to cellular transformation and, hence, tumour formation, his group has examined its effects on mammary epithelial cell behaviour. Although they do observe a reduction in cell adhesion leading to a change in morphology and decreased cell proliferation, the most significant change is a profound apoptotic resistance. This includes a greater resistance to several DNA damaging chemotherapeutic drugs. Mechanistically, this apoptotic resistance occurs through the secretion of a paracrine factor that activates Akt. The increase in Akt signalling subsequently prevents the activation of p53 in response to DNA damage through the ASK1/JNK pathway.
Current experiments in the laboratory seek to identify the Akt-activating secreted factor induced by Notch signalling. They are also looking to identify reliable markers of Notch signalling in breast cancers and to determine how Notch signalling is activated. In the longer term, they wish to determine the therapeutic potential of targeting Notch signalling in the treatment of breast cancer.
Current & Future Projects
- Determining the molecular mechanism by which Dishevelled inhibits Notch signalling and its relevance to cell fate decisions in vertebrates (Anna Collu and Silvia Oliveira)
- Elucidating the points crosstalk between the Notch and Wnt pathways that limit Wnt signalling (Ana Hidalgo Sastre)
- Identifying the secreted factor induced by Notch signalling that activates Akt in human breast cancer
- Understanding how elevated EDAR signalling promotes the transformation of breast epithelial cells