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Examining the biology of breast cancer diagnosed in women aged 40 and under


Project Description

Breast cancer is diagnosed in around 55 000 women in the UK each year. While typically more common after the menopause, some 10 - 12% of breast cancers are diagnosed in women under the age of 40. Unfortunately, young women tend be diagnosed later, usually with more aggressive tumours of higher grade and tend to get higher incidence of triple negative, HER-2 positive and Luminal B cancers, which are all indicators of poorer prognosis. Although a high proportion of this group BRCA1 and BRCA2 mutations, BRCA mutation carriers appear have similar survival as non-carriers. Through multidisciplinary working, we have identified a cohort of nearly 400 breast cancer patients aged 40 and under with a minimum of 10 years follow up, who were diagnosed and treated at NHS Grampian. For many patients we already have the survival and follow up data along with basic pathology. This large cohort provides an excellent platform for further study.

There is now strong evidence supporting the importance of the tumour microenvironment (TME), particularly fibroblasts in influencing tumour progression, metastatic spread and therapeutic response. We hypothesise that the TME is distinct in breast cancer diagnosed under 40 and by exploring this will help understand the biology of this subcohort of patients’ further and might help identify new receptors and markers that can potentially be used to develop future targeted therapy.

Aims
1. Define molecular subtypes of breast cancer in this age group and profile the stromal microenvironment
2. Establish and characterise fibroblasts from prospectively collected tumour samples to use in organotypic co-cultures with tumour cells to define whether fibroblasts modify responses of tumour cells to chemotherapy
3. Use on-line prognostic tools to validate outcome and mine existing databases to identify genetic changes which might be targeted therapeutically

Methods
Tumour phenotype and the stromal microenvironment will be examined using histopathology and digital pathology methods, including application of image analysis algorithms (QuPath) and related to clinical outcome. In addition, to the local Grampian Biorepository, which will facilitate access to clinical samples for the retrospective series, Aberdeen is part of the Breast Cancer Now Tissue Bank (www.breastcancertissuebank.org), facilitating access to a wide range of breast tissue samples and cells collected prospectively. From this, we will establish and hTERT immortalise fibroblasts and employ these in single and co-culture assays to examine how they affect response to typical therapies used in this patient cohort. Online tools e.g. NHS PREDICT (https://breast.predict.nhs.uk/index.html) will be used to validate survival outcomes and using data from the METABRIC, TCGCA and Oncomine platforms will identify genetic changes in breast cancer in the under 40s, potentially uncovering clinically actionable therapeutic targets.

Student experience
The student will develop skills and expertise in laboratory techniques including, but not limited to, 2D and 3D cell culture, cell immortalisation, proliferation and migration assays, immunohistochemistry, digital pathology, and using online algorithms. They will also learn how to mine publicly available data generated elsewhere and will have opportunities to shape the direction of the project. They will join a dynamic multidisciplinary research group, including clinical staff, to ensure the project maintains a translational focus and will have opportunities to attend MDTs. Through our role in the Breast Cancer Now Tissue Bank, they will also gain an understanding of breast cancer biobanking.

APPLICATION PROCEDURE:
Formal applications can be completed online: https://www.abdn.ac.uk/pgap/login.php. You should apply for Degree of Doctor of Philosophy in Medical Sciences, to ensure that your application is passed to the correct person for processing.

NOTE CLEARLY THE NAME OF THE SUPERVISOR AND EXACT PROJECT TITLE ON THE APPLICATION FORM.

Further information on Cancer research at Aberdeen can be found here: https://www.abdn.ac.uk/smmsn/research/cancerabdn-1022.php

Funding Notes

This project is part of a competition funded by the School of Medicine, Medical Sciences and Nutrition for a 4 year PhD programme. Full funding is available to UK/EU candidates only. Overseas candidates can apply for this studentship but will have to find additional funding to cover the difference between overseas and home fees (approximately £15,680 per annum).

Candidates should have (or expect to achieve) a minimum of a 2.1 Honours degree in a relevant subject. Applicants with a minimum of a 2.2 Honours degree may be considered provided they have a Merit/Commendation/Distinction at Masters level.

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