Endocrinology, Oncology, Oestrogen Metabolism, Colorectal Cancer, Breast Cancer, Metabolic inhibitors, Novel in vivo Cancer Modelling.
Oestrogen metabolism and signalling in colorectal cancer
Uncertainty surrounds the actions of oestrogens in colorectal cancers (CRC). Although epidemiological evidence suggests that oestrogens are protective against this malignancy, there is now significant research demonstrating oestrogen action may increase the incidence and proliferation of colorectal cancer. What is clear is that the regulation of oestrogen synthesis and metabolism is important in CRC. Numerous studies indicate that oestrogen receptor b (ERb), which when activated induces apoptosis, is lost during colonic tumourigenesis. We have shown that steroid sulfatase (STS), an enzyme which desulfates conjugated oestrogens to their active forms, is elevated in CRC. Indeed, increased STS activity is related to increased CRC proliferation. It has also been demonstrated that down-regulation of 17b-HSD-2, which oxidises oestradiol (E2) to oestrone (E1), has also been shown to be a negative prognostic factor for CRC mortality, and the ratio between STS and sulfotransferase (SULT1E1), enzymes that de-sulfate and sulfate E1 respectively, is a potent prognostic factor for CRC clinical outcomes. However, much remains unclear due to a lack of basic molecular research. For example, although the STS/EST ratio in CRC patient tissue has implications on mortality, it is unknown how this effects CRC cell growth, E1S/E1/E2 concentrations, and ERa/ERb expression in vitro and in vivo. Furthermore, complete profiling of oestrogenic enzyme expression and activity, which would allow a greater understanding of local oestrogen concentrations, is lacking in available CRC cell lines and patient samples. This information, once ascertained, would clarify how oestrogens influence CRC, potentially leading to new therapeutic avenues for this disease.
Identifying novel inhibitors of oestrogen metabolism
We work with various worldwide research groups on the identification of novel pharmacological inhibitors that block oestrogen metabolism. We provide key assays (Steroid Sulfatase, Sulfotransferase, Aromatase) to identify potent inhibitors of these enzymes. We anticipate these inhibitors will be useful for the treatment of oestrogen-dependent cancers.
Unravelling the steroid metabolome in ovarian cancer
We are in the early stages of identifying potential early detection diagnostic tests for ovarian cancer. Early detection of this malignancy is key to improving patient survival rates. Thus, we are examining the steroid profile of ovarian cancer tissue and of the patients’ urine and serum to identify novel biomarkers for the disease.
Research groups and Centres
Institute of Metabolism and Systems Research
University of Birmingham collaborators:
- Prof Wiebke Arlt
- Dr Rowan Hardy
- Dr Jonathan Mueller
- Dr Sudha Sundar
- Dr Andrew Beggs
- Dr Liam Cox
- Dr Angela Taylor
- Dr Dan Tennant
- Dr Vas Chortis
- Dr David Jeevan
- Prof Barry Potter (University of Oxford)
- Dr Atul Purohit (Imperial College London)
- Dr Douglas Gibson (University of Edinburgh)
- Prof Philippa Saunders (University of Edinburgh)
- Dr Christopher Ireson (Pharmidex Ltd.)
- Prof Lou Metherill (Queen Mary’s University, London)
- Prof Ulrike Grienke (University of Vienna, Austria)
- Prof Judith Rollinger (University of Austria)
- Dr Mohammad El-Gamal (University of Sharjah, UAE)
- Dr Mark-Henry Pitty (Oregon Therapeutics, Paris, France)