Short-Term\nExposure\nto Foodborne Xenoestrogens Affects\nBreast Cancer Cell Morphology and Motility Relevant for Metastatic\nBehavior <i>In Vitro</i>

Breast cancer is\nhighly susceptible to metastasis formation. During\nthe time of disease progression, tumor pathophysiology can be impacted\nby endogenous factors, like hormonal status, as well as by environmental\nexposures, such as those related to diet and lifestyle. New lines\nof evidence point toward a potential role for foodborne endocrine\ndisruptive chemicals in this respect; however, mechanistic understanding\nremains limited. At the molecular level, crucial steps toward metastasis\nformation include cell structural changes, alteration of adhesion,\nand reorganization of cytoskeletal proteins involved in motility.\nHence, this study investigates the potential of dietary xenoestrogens\nto impact selected aspects of breast cancer cell mechanotransduction.\nTaking the onset of the metastatic cascade as a model, experiments\nfocused on cell-matrix adhesion, single-cell migration, and adaptation\nof cell morphology. Dietary mycoestrogens alternariol (AOH, 1 μM)\nand α-zearalenol (α-ZEL, 10 nM), soy isoflavone genistein\n(GEN, 1 μM), and food packaging plasticizer bisphenol A (BPA,\n10 nM) were applied as single compounds or in mixtures. Pursuing the\nhypothesis that endocrine active molecules could affect cell functions\nbeyond the estrogen receptor-dependent cascade, experiments were performed\ncomparing the MCF-7 cell line to the triple negative breast cancer\ncells MDA MB-231. Indeed, the four compounds functionally affected\nthe motility and the adhesion of both cell types. These responses\nwere coherent with rearrangements of the actin cytoskeleton and with\nthe modulation of the expression of integrin β1 and cathepsin\nD. Mechanistically, molecular dynamics simulations confirmed a potential\ninteraction with fragments of the α1 and β1 integrin subunits.\nIn sum, dietary xenoestrogens proved effective in modifying the motility\nand adhesion of breast cancer cells, as predictive end points for\nmetastatic behavior <i>in vitro</i>. These effects were\nmeasurable after short incubation times (1 or 8 h) and contribute\nto shed novel light on the activity of compounds with hormonal mimicry\npotential in breast cancer progression.