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  3. Plant sterols as modifiers of oxysterol metabolism in triple negative breast cancer relapse

Research project

Plant sterols as modifiers of oxysterol metabolism in triple negative breast cancer relapse

  • Start date: 1 October 2017
  • End date: ongoing
  • Value: 146,200
  • Partners and collaborators: Dr Darren Greenwood
  • Primary investigator: Dr James L Thorne
  • Co-investigators: Dr Thomas Hughes, Dr Giorgia Cioccoloni, Dr Nisha Sharma
  • External co-investigators: Dr Hanne Roberg Larsen (University of Oslo)
  • Postgraduate students: Chrysa Soteriou, Samantha Hutchinson, Alex Websdale, Priscilia Lianto

Plant sterols as modifiers of oxysterol metabolism in triple negative breast cancer relapse | Faculty of Environment | University of Leeds

Funder: Breast Cancer Action (Leeds Cares)

Several different types of cell in the human body including immune cells and fat cells, are able to convert cholesterol into a range of other molecules. In people with high levels of bad cholesterol (LDL-C), conversion of cholesterol is altered and leads to a build up of damaging intermediate molecules, termed oxysterols. These oxysterols can be secreted out of the cell and taken up by different cell types around the body. If the concentration of oxysterols is too high then cancer growth can be enhanced because oxysterols promote DNA damage, confer resistance to a range of chemotherapy drugs and help tumours to spread.

Some breast cancer types recruit these oxysterol producing cells which then colonise the tumour leading to high levels of oxysterols within the local cancer environment. How these other cells help breast tumours metastasize or resist chemotherapy is not well understood, but epidemiological and clinical studies suggest elevated LDL-C is associated with worse survival, poorer response to therapy and an increased propensity for disease relapse in breast cancer patients.

In this trial the investigators will test how an LDL-C lowering dietary intervention (using commercially available phytosterol added food products), alters the ability of non-cancer cells (adipocytes, fibroblasts and macrophages) collected from high LDL-C volunteers to change chemotherapy response and metastatic process in breast cancer cells. Volunteers with high LDL-C levels will be recruited by the University of Leeds, and divided randomly into two arms that cross over.

The experimental period (yogurt drink enriched with phytosterols) and placebo period (non-enriched yogurt drink) will each last for 8 weeks, alternated with a 4 weeks of wash-out period. Samples will be collected 4 times (week-0, week-8, week-12, week-20) during the study and will include blood, white blood cells (macrophages), and fat tissue cells. Measurements will include oxysterol, LDL-C and phytosterol concentrations (volunteers' serum/plasma, media from the host cells/breast cancer experimental culture) and how the host cells alter the behaviour of cancer cells in the laboratory.

Publications and outputs

  1. 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).
     
  2. 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 2. Cioccoloni G, Soteriou C, Websdale A, Wallis L, Zulyniak MA, and Thorne JL* (2020).
     
  3. Phytosterols and phytostanols and the hallmarks of cancer: a systematic review and meta-analysis of whole organism models. Critical Reviews in Food Science and Nutrition. doi: 10.1080/10408398.2020.1835820
     
  4. 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.
     
  5. Hutchinson SA, Lianto P, Moore JB, Hughes TA, Thorne JL* (2019). Phytosterols Inhibit Side-Chain Oxysterol Mediated Activation of LXR in Breast Cancer Cells. Int J Mol Sci 20(13). doi.org/10.3390/ijms20133241
     
  6. 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. 6. Fakih O, Sanver D, Kane D, Thorne JL* (2018).
     
  7. Exploring the biophysical properties of phytosterols in the plasma membrane for novel cancer prevention strategies. Biochimie. Oct;153:150-161

Project website

https://clinicaltrials.gov/ct2/show/NCT04147767