About the Project
Obesity is a well-known risk factor for breast cancer development in the postmenopausal setting. Paradoxically, this risk is decreased in pre-menopausal women. Inflammation is also associated with obesity with chronic inflammation observed in several different types of cancer, including breast, however younger women appear protected from adipose inflammation. Breast cancer also affects a small number of men and typical behaves like post-menopausal female breast cancer; we have demonstrated links between obesity and adiposity in male breast cancer (1). Adipocytes, fibroblasts and immune cell infiltrates, notably macrophages, reside within the tumour microenvironment (TME), collectively comprising the stroma, which can influence the behaviour of neighbouring cells. Macrophages that contribute to the inflammatory state are frequently recruited into adipose tissue, forming crown-like structures, which are increased in breast tissue of obese individuals (1,2). Previously fibroblasts, the main cellular component of the TME, were believed to be responsible for influencing epithelial cell behaviour, however there is growing recognition that adipocytes may be more important in driving epithelial cell growth, cancer cell invasion and therapy resistance. In the post-menopausal setting adipocytes are responsible for estrogen biosynthesis through in situ aromatisation of androgens, also secreting multiple other endocrine and paracrine factors. Different adipose depots contain several different types of adipocytes with distinct properties (3). Recent data suggest that increased epithelial-adipose tissue crosstalk may create an environment which favours breast cancer development (4). Furthermore, transcriptomic profiling showed increased expression of several genes associated with lipid metabolism and adipogenesis. This multidisciplinary project will test the hypothesis that hormonal backgrounds congruent with pre- and post-menopausal settings, influence the adipose-inflammatory microenvironment resulting in repression or enhancement of tumorigenesis, respectively. We will use multiple analyses of adipose and inflammatory cell function combined with cutting edge 3D tissue models, developed by the PI (5,6) to dissect the mechanisms behind these paradoxical effects.
1. Evaluate the presence, distribution and abundance of proteins involved with lipid metabolism and adipogenesis (e.g. steroid metabolising enzymes, cytokines/adipocytokines, prostaglandins) in pre- and post-menopausal female breast cancer with known body mass index using immunohistochemistry and image analysis
2. Determine if the phenotype of breast adipose tissue that is associated with cancer is independent of inflammatory responses in other adipose depots
3. Increase the complexity of existing 3D multicellular in vitro models to incorporate mature adipocytes, derived from pre- and post-menopausal normal-weight or obese women, and macrophages polarised toward a M1 phenotype
4. Use these models to perform functional assays (knockdown/overexpression of key genes. informed from aim 1) to determine effects on cell phenotype (proliferation, migration and invasion) to provide mechanistic insight into the early stages of breast cancer development
You will join a multidisciplinary team of scientists, pathologists and clinicians and attend meetings of the Aberdeen Breast Team, a group of clinical, laboratory, biobanking and nursing staff involved in translational breast cancer research, providing valuable clinical insight for this work. You will receive training in cutting edge techniques, including use of tissues and cells derived from local and national biorepositories (www.breastcancertissuebank.org) to generate 3D multicellular human breast tissue models to test experimental hypotheses, alongside various molecular, cellular, histological/immunohistochemical techniques plus image analysis and database mining. Collectively these will provide mechanistic insight into how the adipose-inflammatory axis contributes to, or protects from, breast carcinogenesis.
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.
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 as Master's level.
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