Fluid Flow Simulation Upregulates Expression S100 Genes During Breast Cancer Development and Progression

Kenneth Fuh, Jessica Withell, Robert Shepherd, Kristina Rinker

Abstract


S100 proteins are intracellular Ca2+ sensors that participate in a range of biological processes including proliferation, invasion and differentiation. Overexpression of S100 genes has been observed in breast carcinomas. However, their roles during breast cancer initiation and progression have not been defined. The objective of this study was to analyze changes in gene expression profiles of S100 genes upon exposing human mammary epithelial cells (HMECs) to fluid flow. Relevant findings were correlated in gene profiles from clinical datasets.
A bioreactor system consisting a parallel-plate flow chamber was used to expose HMECs to fluid shear stress, simulating exposure of cells to blood vessels during breast cancer initiation and progression. Total RNA from flow exposed cells and cells grown in static conditions was isolated. Differentially expressed genes were quantified using Affymetrix microarrays and RT-qPCR.
Expression data showed more than 5 fold upregulation of S100P and S100A7 with flow stimulation. Consistent overexpression of S100 genes was also observed in ductal carcinoma in situ patient tissue compared to healthy breast, suggesting roles in breast cancer initiation. Kaplan –  Meier curves of breast cancer patients (n=936), demonstrate that elevated expression of S100A7 and S100P correlate with reduced survival times.
This study shows that exposing HMECs to fluid flow upregulates genes identified clinically to be overexpressed during breast cancer initiation and progression, including S100A7 and S100P. This suggests that our bioreactor platform is a useful tool for identifying how mammary epithelial cell exposure to blood flow affects breast cancer initiation and early stages of disease progression.



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