Di(2-ethylhexyl) phthalate (DEHP) increases proliferation of epithelial breast cancer cells through progesterone receptor dysregulation.

The di(2-ethylhexyl) phthalate (DEHP) is a plasticizer incorporated to plastic matrices of widely used consumer products. However, it is gradually released from these products, resulting in a chronic exposure for humans. Although DEHP, similar to other members of the phthalates family, is generally considered as an endocrine disruptor, the mechanisms implicated in its toxicity are yet poorly understood. Our objective was to determine the effects of an exposure to DEHP and to one of its major metabolite, the mono(2-ethylhexyl) phthalate (MEHP) on markers involved in breast carcinogenesis. T-47D cells were exposed to environmentally relevant and higher doses of DEHP and MEHP (0.1-10 000 nM) for 4 days. Our results showed that an exposure to 10 000 nM of DEHP and 0.1 nM of MEHP significantly increased the proliferation of T-47D cells, without inducing apoptosis. In addition, a significant increase in the protein levels of the isoform A of the progesterone receptor (PR) and of nuclear levels of PR were observed in T-47D cells exposed to 10 000 nM of DEHP. Importantly, the increased proliferation and nuclear levels of PR were totally and partially inhibited, respectively, by Mifepristone, a PR antagonist. These results suggest that an exposure to DEHP or MEHP increase cell proliferation by activating PR signaling, which could potentially increase the risks to develop breast cancer. The mechanism of activation of the progesterone pathway by DEHP and the long-term consequences of this activation remained to be elucidated.

Chronic exposure to hexachlorobenzene results in down-regulation of connexin43 in the breast.

Decreased expression of connexins has been associated with cancer, but the underlying mechanisms are poorly understood. We have previously shown that a 5 day exposure to hexachlorobenzene (HCB) resulted in decreased connexins expression in hepatocytes 45 days later, and that this down-regulation was linked to activation of Akt through the ILK pathway. Because HCB promotes cancer in both the liver and breast, the present study aimed to determine if the mechanisms are similar in both tissues. MCF-12A breast cells were thus transfected with vectors coding for either Akt or a constitutively active form of Akt. In those cells, activation of Akt was correlated with decreased Cx43 levels. Female rats were then exposed to HCB by gavage either following the same protocol used previously for the liver or through a chronic exposure. While no changes were observed after the 5 days exposure protocol, chronic exposure to HCB resulted in increased Akt levels and decreased Cx43 levels in breast cells. In vitro, Akt was activated in MCF-12A cells exposed to HCB either for 7 days or chronically, but no changes were observed in junctional proteins. Together, these results suggested that, while activation of Akt can decrease Cx43 expression in breast cells in vitro, other mechanisms are involved during HCB exposure, leading to a decrease in Cx43 levels in a model- and duration-dependent manner. Finally, we showed that HCB effects are tissue specific, as we did not observe the same results in breast and liver tissues.