Multifactorial impacts on early breast carcinogenesis-assessing the combined effects of mixtures of endocrine disrupting chemicals and fatty acids

Abstract

The percentage of breast cancer attributed to genetic factors is estimated to be between 5-10%, suggesting that a large proportion of breast cancer cases can be attributed to external factors. There has been extensive research on external factors such as obesity, alcohol, smoking, physical activity, diet and environmental chemicals and their role in breast cancer development. However, the evidence of environmental chemicals such as Endocrine Disrupting Chemicals (EDCS) on breast cancer initiation has been inconclusive because they have been studied as single compounds at concentrations not reflective of tissue concentrations. This phenomenon is also applicable to other risk factors, such as diet, suggesting that several multiple risk factors interact to initiate breast carcinogenesis. Using a non-tumorigenic cell line, MCF-12A, in// a 3D model that recapitulates human mammary structure, mixtures of thirteen EDCs and four fatty acids were tested at tissue concentrations for their effect on breast carcinogenesis. The results showed that the mixtures disrupted acini formation and affected genes and pathways involved in carcinogenesis, such as cell proliferation, migration and apoptosis. There were increases in the sizes of acini and decreases in circularity, which are markers of neoplastic transformation. Changes to gene expression and pathways involved in breast cancer were also found when BRCA1-silenced MCF-12A cells were exposed to mixtures of EDCs and fatty acids, suggesting a possible increase in absolute risk for people with a familial mutation in the BRCA1 gene. The ability of 3D models to appropriately model processes involved in normal cellular functions such as proliferation and glycolysis was also demonstrated through a meta-analysis of published data. Overall, we show that exposure to mixtures of EDC and fatty acids can increase induce genes and pathways that can lead to breast carcinogenesis. We also demonstrated the ability of EDCs to induce the expression of carcinogenic genes in BRCA1 silenced cells, suggesting a possible increase in breast cancer risk.