Mechanism of action of endocrine disruptors on human breast cancer cells and animal models

ANDREA RANDI

Buenos Aires

Congreso; 11th SETAC Society of Environmental Toxicology and Chemistry Latin America Biennial Meeting; 2015

Sociedad de Toxicología y Química Ambiental Latinoamericana

Exposure to ubiquitous persistent organic pollutants (POPs) such as polychlorinated biphenyls and hexachlorobenzene (HCB) has attracted attention in breast cancer etiology. Although the mechanistic actions of these chemicals in carcinogenesis remain unclear,studies showed that some POPs have the potential to promote cancer development in various experimental models. These chemicals are endocrine-disrupting compounds, which interfere with the physiology of normal endocrine-regulated events and have two important characteristics make them different from many non-endocrine toxicants: low-dose effects and non-monotonic response curves. Hexachlorobenzene (HCB) is a widespread organochlorine pesticide found in maternal milk and in lipid foods. It is a dioxin-like compound and a weak ligand of the aryl hydrocarbon receptor (AhR) protein. AhR is a transcription factor that regulates gene expression associated with proliferation, angiogenesis,migration and invasion. HCB is a tumor co-carcinogen in rat mammary gland and an inducer of cell proliferation in MCF-7 positive estrogen receptor alpha (+ERα) human breast cancer cells.We have demonstrated that HCB stimulates c-Src/epidermal growth factor receptor (HER1)/STAT5b and HER1/ERK1/2 signaling pathways and cell migration in human breast cancer cell line MDA-MB-231 (-ERα).Ourpreviousstudies using MDA-MB-231 show that HCB enhances metalloprotease-2 (MMP2) expression, as well as cell invasion, through AhR, c-Src/HER1 pathway. Moreover, HCB increases MMP9 expression, secretion and activity through a HER1 and AhR-dependent mechanism. HCB enhances subcutaneous tumor growth in MDA-MB-231 and C4-HI in vivobreast cancer models in mice. Furthermore, HCB stimulates lung metastasis regardless the tumor hormone-receptor status. In a recent investigation, we found that HCB inducesthe angiogenic switch and increases vascular endothelial growth factor (VEGF) expression in a xenograft model. Human microvascular endothelial cells (HMEC-1) exposed to HCB showed an increase in cyclooxygenase-2 (COX-2), VEGF and AhR expression. In addition, we found that HCB activates VEGF-Receptor 2 (VEGFR2) downstream pathways p38 and ERK1/2. HCB induces cell migration and neovasculogenesis in anAhR, COX-2 and VEGFR2-dependent manner. These results may help to understand the association among HCB exposure, angiogenesis and mammary carcinogenesis. Our findings suggest that HCB may be a risk factor for human breast cancer progression.