Interactions between the IGF system and cholesterol metabolism in breast cancer
Proliferating cancer cells are believed to have increased requirements for cholesterol: tumour cells can increase lipid biosynthesis, in addition to taking up cholesterol from the bloodstream. Abnormal cholesterol accumulation is a characteristic of some malignancies and inhibiting cholesterol storage machinery in breast cancer cell lines was associated with reduced proliferation(1). The capacity of breast cancer cells to use exogenous lipids may explain the link between high fat diets with breast cancer onset and progression (2). The IGF system is key in regulating growth and metabolism, and is thought to mediate the effects of nutrition on these processes. It is comprised of 2 ligands (IGF-II and IGF-II), their receptors (type 1 IGF-IR and IGF-II/mannose 6-phosphate receptor) and six high affinity IGF-binding proteins (IGFBP-1 to 6). Evidence indicates that the IGF axis has an important role in breast development and in mediating how nutrition may lead to disease progression (3). This PhD will test the following hypothesis: increased circulating LDL and increased IGF activity work in synergy to increase cholesterol ester accumulation, PI3K/AKT signalling, to promote breast cancer progression. This project will utilise a range of techniques including cell culture of breast cell lines (normal and malignant), cell proliferation, western immunoblotting, immunoprecipitation, the assessment of apoptosis, PCR, metabolic assessment (MTT), colony formation assays, migration assays, invasion assays, immunocytochemistry, immunohistochemistry and cell fractionation of whole cell lysates.
When applying please select ’Medicine PhD’ within the Faculty of Health Sciences.
1. dos Santos CR, Domingues G, Matias I, Matos J, Fonseca I, de Almeida JM, Dias S1. LDL-cholesterol signaling induces breast cancer proliferation and invasion. Lipids Health Dis. 2014; 13:16
2. Rodrigues Dos Santos C1, Fonseca I, Dias S, Mendes de Almeida JC. Plasma level of LDL-cholesterol at diagnosis is a predictor factor of breast tumor progression. BMC Cancer 2014; 14:132
3. Belardi V1, Gallagher EJ, Novosyadlyy R, LeRoith D. Insulin and IGFs in obesity-related breast cancer J Mammary Gland Biol Neoplasia 2013; 18(3-4):277-89.