- Start date: 1 January 2017
- End date: open
- Value: £60,000
- Partners and collaborators: Funded by breastcanceruk.org.uk
- Primary investigator: Dr James L Thorne
- Co-investigators: Dr Thomas Hughes, Dr Giorgia Cioccoloni
- External co-investigators: Dr Hanne Roberg Larsen (Oslo)
- Postgraduate students: Samantha Hutchinson, Alex Websdale
Many breast cancers are thought to be preventable through diet and lifestyle choices. Obesity and elevated cholesterol are risk factors for breast cancer initiation and progression, but exact mechanisms are not understood fully. Cholesterol levels are influenced by a variety of dietary and lifestyle factors, and high LDL-cholesterol has been linked to failure of cancer therapy.
The cholesterol metabolic pathway is altered in breast cancer, leading to increased products, known as oxysterols, some of which may promote tumour progression. Non-cancer “host” cells such as fat cells (adipocytes), support cells (fibroblasts) and immune cells (macrophages) convert cholesterol into oxysterols which are released into the surrounding tumour micro-environment.
Oxysterols are then taken up by adjacent breast cancer cells and may trigger biochemical pathways which lead to chemotherapy resistance and breast cancer spread. Host cells produce oxysterols under normal conditions, but it is unclear to what extent production is altered when these cells are in a cancerous environment. Each of the cell types of the tumour micro-environment exhibit their own potential for oxysterol production by making different amounts of oxysterol-producing and catabolising enzymes.
This project explores the hypothesis that oxysterols, released by non-cancer host cells into the tumour micro-environment, are taken up by adjacent breast cancer cells, eventually leading to chemotherapy resistance and tumour spread.
As oxysterols may promote tumour progression, interventions which interfere with their production may prevent breast cancer relapse. This work is also investigating whether a dietary intervention can alter oxysterols produced by host cells, thereby preventing breast cancer recurrence.
Publications and outputs
- Hutchinson SA€, Websdale A€, Cioccoloni G, Røberg-Larsen H, Lianto P, Kim B, Rose A, Soteriou C, Wastall LM, Williams BJ, Henn MA, Chen JJ, Ma L, Moore JB, Nelson E, Hughes TA* and Thorne JL* (2021). Liver x receptor alpha drives chemoresistance in response to side-chain hydroxycholesterols in triple negative breast cancer. Oncogene doi.org/10.1038/s41388-021-01720-w
- Hutchinson SA, Lianto P, Roberg-Larsen H, Battaglia S, Hughes TA, Thorne JL* (2019). ER-Negative Breast Cancer Is Highly Responsive to Cholesterol Metabolite Signalling. Nutrients. 11. doi:10.3390/nu11112618.
- Solheim S, Hutchinson SA, Lundanes E, Wilson SR, Thorne JL* and Roberg-Larsen H* (2019). Fast liquid chromatography-mass spectrometry reveals side chain oxysterol heterogeneity in breast cancer tumour samples. J Steroid Biochem Mol Biol. Sep; 192;105309.