Short-Term Exposure to Foodborne Xenoestrogens Affects Breast Cancer Cell Morphology and Motility Relevant for Metastatic Behavior In Vitro.

Abstract

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