Dr S Howell, Prof Robert Clarke, Dr M Sherratt
No more applications being accepted
Competition Funded PhD Project (Students Worldwide)
About the Project
Tamoxifen (TAM) reduce the incidence of breast cancer (BC) by approximately 40%. However, all of the reduction in risk is seen in women who experience a reduction in mammographic density during the first year of treatment. Mammographic density is thus a powerful predictive biomarker of resistance to chemoprevention with TAM. We have recently shown that mammographic density is primarily associated with collagen organisation rather than abundance. Such periductal fibrillar collagen increases tissue stiffness and is a key mediator of mammary carcinogenesis in rodents. In this project we seek to identify the molecular mechanisms underlying mammographic density and to investigate how they change in response to TAM. By examining the patterns of response in responding vs resistant breast tissue we hope to identify novel agents that will reverse resistance and thus prevent more cases of BC in the future.
Women commencing tamoxifen chemoprevention will have biopsies of the breast prior to and after 1 month of treatment. RNA-Seq bioinformatic analysis will identify the gene networks differentially expressed in resistant vs sensitive breasts. In collaboration with the CRUK MI Drug Discovery Unit chemo-informatic screening of the FDA panel of drugs will identify lead compounds for repurposing into prevention. Proteomic analysis will identify differential protein composition and the relationship between TAM sensitivity and tissue micro-structural and mechanical stiffness will be characterised by atomic force microscopy and micro-computed tomography (microCT). An architecturally intact whole tissue in vitro culture model of normal breast tissue will be developed that faithfully recapitulates in vitro the changes in gene expression seen in response to TAM in vivo. The candidate chemoprevention agents will then be tested in this model with the aim of identifying a lead candidate for translation in to a pilot prevention trial.
This Clinical Research Training Fellowship will be funded by the CRUK Manchester Centre, and are usually three years in length, with the option to extend to four years under certain circumstances.
Please formally apply via the University of Manchester online system, and select PhD Cancer Sciences. Include your CV, two reference letters (or names of referees) with a covering letter (500 - 750 words max) indicating your first choice project and explaining why you want to apply. Please also comment on your suitability for the post, giving an overview of your relevant experience and training.
More information about the CRUK Manchester Centre PhD Training Scheme, including the application process, can be found on our website: http://crukcentre.manchester.ac.uk/Training/PhD-Training-Scheme.
Funding Notes
The Fellowship will cover an annual stipend (currently at £19,000 per annum), running expenses and PhD tuition fees at UK/EU rates. Where international student fees are payable, please provide evidence with your application of how the shortfall will be covered (approximately £16,000 per annum).
All applicants must:
• hold a minimum upper second class (or equivalent) undergraduate degree in relevant subject
• be post-registration clinicians and ideally have a specialist training post
• have been resident and worked within the EEA (European Economic Area) for at least three years prior to application
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