Upregulation of COX-2 in MCF7 Breast Cancer Cells When Exposed to Shear Stress

Abstract

Background: Invasive breast cancer affects 1 in 8 women in the United States and causes one of the highest cancer mortality rates for women. Cyclooxygenase-2 (COX-2), a central enzyme in prostaglandin biosynthesis, is implicated in breast cancer initiation, progression, invasion, metastasis, and has been implicated in mechanotransduction of breast cancers. However, it is not currently known if shear stress mediated mechanotransduction is mediated by COX2. Therefore, in this report, we hypothesized that COX2 modulates shear stress mechanotransduction in luminal A breast cancer cells, causing proliferation of tumor cells and chemoresistance. Methods: In order to probe this hypothesis, we utilized a bioreactor capable of stimulating tumor cells with variable shear stress in a 3D microenvironment and investigate d the influence of shear stress stimulus on MCF7A breast cancer cells. Tumor cells were encapsulated within a hydrogel composed of agarose and collagen type I and placed under pulsatile shear stresses of 3.04 or 3.25 dynes/cm2. Shear stress stimulation was conducted for 24 hours and compared with the non-stimulated 3D cultured cells. Shear stresses were quantified using COMSOL finite element modeling. Results: MCF7 cells exposed to shear stress were discovered to increase cellular area and proliferation, displaying enhanced invasive potential and cancer progression. Shear stress stimulated cells also significantly upregulated a variety of genes influencing metastasis and chemoresistance, but most significantly COX2. Treatment with celecoxib, a selective inhibitor of COX-2 showed effective downregulation of COX-2 expression at gene and protein level. Additionally, shear stress stimulated cells displayed enhanced resistance to paclitaxel treatment. Conclusions: Taken together these results demonstrate the role of COX-2 in enhancement in breast cancer disease progression under shear stress stimulation.