The missing link: endocrine disrupting chemicals, epigenetics and breast cancer risk

This thesis was submitted for the award of Doctor of Philosophy and was awarded by Brunel University LondonEvidence suggests that 26.8% of new breast cancer cases can be attributed to extrinsic influences, such as lifestyle and environmental factors. Whilst we have increased knowledge surrounding factors like alcohol and obesity, little is known regarding environmental pollutants, such as endocrine disrupting chemicals (EDCs), which are defined by their ability to interfere with the regulation of an individual’s endocrine system. Research has so far proven inconclusive, with effects only observed at concentrations considerably higher than those present in human tissues and in unrepresentative assay systems. Utilising 3D in vitro assays that recapitulate characteristics of the human mammary gland, the relationship between low-dose EDC exposures (comparable to concentrations found in human tissues) and breast carcinogenesis was investigated. This work showed, both in primary cells and in the ER-positive MCF-12A cell line, that EDCs can affect acini development, gene expression and DNA methylation. Changes were indicative of neoplastic transformations, including increases to acini size and loss of circularity. Genetic and epigenetic modifications to genes associated with breast tumourigenesis, such as cell cycle regulators and tumour suppressors, were observed at concentrations relevant to human exposures. Similar changes were seen in predisposed individuals with a BRCA1 mutation, translating into a significant impact on absolute risk of breast cancer. The ability of chemical mixtures to increase breast cancer risk was also considered. When combined at concentrations in human tissues, four EDCs (dichloro-diphenyl-trichloroethane, benzophenone 3, bisphenol A and propylparaben) acted together to produce a significant effect, by disrupting acini formation and gene expression. These findings demonstrate the capacity of EDC exposures to contribute to breast cancer risk. Increasing our understanding of chemical contributions to cancer development provides opportunities for cancer prevention and more comprehensive risk model development. Results demonstrate a need for further research in this area and act as a foundation for future studies