Loss of epithelial cell polarity promotes cell invasion and cancer dissemination. Therefore, identification of factors that disrupt polarized acinar formation is crucial. Reactive oxygen species (ROS) drive cancer progression and promote inflammation. Here, we show that the non-polarized breast cancer cell line T4-2 generates significantly higher ROS levels than polarized S1 and T4R cells in three-dimensional (3D) culture, accompanied by induction of the nuclear factor κB (NF-κB) pathway and cytokine expression. Minimizing ROS in T4-2 cells with antioxidants reestablished basal polarity and inhibited cell proliferation. Introducing constitutively activated RAC1 disrupted cell polarity and increased ROS levels, indicating that RAC1 is a crucial regulator that links cell polarity and ROS generation. We also linked monocyte infiltration with disruption of polarized acinar structure using a 3D co-culture system. Gain- and loss-of-function experiments demonstrated that increased ROS in non-polarized cells is necessary and sufficient to enhance monocyte recruitment. ROS also induced cytokine expression and NF-κB activity. These results suggest that increased ROS production in mammary epithelial cell leads to disruption of cell polarity and promotes monocyte infiltration.
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This study was supported by start-up funding from the Markey Cancer Center and funding support from the American Heart Association (12SDG8600000 to R.X.), U.S. Department of Defense (W81XWH-15-1-0052 to R.X.). L.L. was supported by a joint PhD scholarship (201406170144) from the China Scholarship Council.
Supplementary information available online at http://jcs.biologists.org/lookup/doi/10.1242/jcs.186031.supplemental
Li, Linzhang; Chen, Jie; Xiong, Gaofeng; St. Clair, Daret K.; Xu, Wei; and Xu, Ren, "Increased ROS Production in Non-Polarized Mammary Epithelial Cells Induces Monocyte Infiltration in 3D Culture" (2017). Markey Cancer Center Faculty Publications. 77.