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.