Dr S Howell, Prof E Crosbie, Dr Michelle Harvie, Prof Robert Clarke
No more applications being accepted
Competition Funded PhD Project (European/UK Students Only)
About the Project
Obesity is one of the strongest modifiable risk factors for postmenopausal breast cancer and endometrial cancer, the 1st and 4th most common tumours in women respectively. Previous studies in Manchester demonstrate that significant weight reduction by energy restriction results in differentiation of breast epithelium and inhibition of PI3K pathway activity in the endometrium. There is a pressing need to define the cellular and molecular pathways of obesity-induced cancer more precisely in order to develop new approaches to risk reduction in addition to weight loss.
Preclinical studies suggest that breast and endometrial cancers originate from epithelial progenitor populations, however, the impact of weight loss on the cellular hierarchies and stromal interactions at the cellular and molecular level have not been extensively studied in women.
The basis of the proposed study is a randomised trial of three months of a very low energy weight loss diet v control in obese women at elevated risk of breast and endometrial cancers. Biopsies of the breast and endometrium will be taken before and after the intervention. Cellular studies will include the primary endpoint of breast and endometrial proliferation (Ki67) in fixed tissue with dual immunofluorescence (IF) for progenitor cell markers (eg LGR5/SOX9/KIT) and Ki67. Vacuum assisted biopsies provide sufficient breast tissue for detailed analysis of cellular hierarchy through FACS analysis/sorting and functional assays. Gene expression will be used to determine transcriptional changes induced by the diet. The impact of weight loss /energy restriction on local (stromal) and systemic inflammation will be assessed through measurement of inflammatory mediators in tissue and serum. Women will be followed to one year for assessment of adherence to the low energy diet maintenance.
The original data obtained, on the cellular and molecular impact of the diet in two organs with strong links to obesity induced carcinogenesis, will enable identification of novel molecular mechanisms that can be targeted to reduce cancer incidence amongst obese subjects.
All applicants must:
• hold an undergraduate degree in medicine
• 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
Funding Notes
The clinical fellowships are usually tenable for three years, although in certain circumstances they may be four years duration. We will provide running expenses, an appropriate salary in line with the applicant’s current salary and grade, and full coverage of University PhD fees. Where international student fees are payable, please provide evidence with your application of how the shortfall will be covered (approximately £17,000 per annum).
As an equal opportunities institution we welcome applicants from all sections of the community regardless of gender, ethnicity, disability, sexual orientation and transgender status. All appointments are made on merit.
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