Unraveling the roles of estrogen receptor alpha and retinoic acid receptor alpha signaling in perfluorinated iodine alkane-mediated migration of breast cancer cells.

Investigating the roles of diverse nuclear receptors in the toxicological effects induced by perfluorinated iodine alkanes (PFIs) is critical, given their (ant)agonistic activities on estrogen receptors (ERs) and retinoic acid receptor alpha (RARα). In this study, two PFIs, namely tridecafluorohexyl iodide (PFHxI) and dodecafluoro-1,6-diiodohexane (PFHxDI), were evaluated for their impacts on the malignancy of breast cancer cells. The in vitro and in silico results revealed PFIs induced ERα agonism and RARα antagonism. Both PFIs remarkably promoted the migration, invasion, and proliferation of MCF-7 cells, while they had negligible effects on MDA-MB-231 cells. The pro-migratory effects of PFIs on MCF-7 cells were abolished by an ERα antagonist of 4-hydroxytamoxifen, indicating the substantial role of ERα signaling in cancer cell progression. The RAR agonist, all-trans retinoic acid (atRA), remarkably inhibited the migration of MCF-7 and RARα-overexpressed MDA-MB-231 (namely, MDA-RARα) cells, indicating RARα agonism lowered the malignancy of tumor cells. Although PFI-induced RARα antagonism alone had no effects on the migration of MDA-RARα cells, it did recover that compromised by atRA. This study provides new evidence on the promotion effects of PFIs on breast cancer cells, and reveals the multi-nuclear receptor-regulated mechanisms for understanding intricate toxicological effects of emerging pollutants.