Epithelial-Mesenchymal Transition: A Special Focus on Phthalates and Bisphenol A.

Epithelial-mesenchymal transition (EMT) is a process during which epithelial cells lose their polarity and ability to adhere. Instead, they gain properties to move, migrate through the extracellular matrix, become invasive, and finally become mesenchymal stem cells. This trans-differentiation is critical for embryo development, wound healing, and stem cell behavior. However, this same phenomenon is also observed in cancer progression. Phthalates and bisphenol A (BPA) are endocrine-disrupting chemicals (EDCs) that are linked to complex human diseases. These chemicals are suggested to disrupt normal hormonal balance (usually by existing estrogenic/antiandrogenic properties) and stimulate the development of reproductive tumors and steroid hormone-dependent cancers, such as breast cancer. Di(2-ethylhexyl) phthalate (DEHP), the most abundant phthalate, was shown to induce DNA damage in human cells via multiple molecular signals that include altered apoptosis and mitotic rate, increased cell proliferation, tumor mobility, and invasiveness of tumor cells. DEHP was also shown to inhibit gap junction intercellular communication and tight junctions and promote EMT. Phthalates may also cause the proliferation and metastasis of cancer cells and tumor progression via up-regulating histone deacetylase 6 (HDAC6). Phthalates can activate peroxisome proliferator activated receptors (PPARs) that may eventually lead to high proliferation of cancer cells. However, in ovarian cells the expression of Snail, Slug, and vimentin was enhanced by the treatment of BPA, whereas E-cadherin was decreased. Mechanistic studies are needed to show the underlying mechanisms of EMT caused by different EDCs.