Abstract
Background and Objective: Matricellular proteins modulate the micro environment of tumors and are recognized to contribute to tumor cell invasion and dissemination. The cysteine-rich angiogenic inducer 61 (CYR61) is upregulated in mesenchymal transformed and invasive breast cancer cells. CYR61 correlates with poor prognosis of breast cancer patients. The signaling mechanism that causes invasive properties of cancer cells regarding to epithelial-mesenchymal transition (EMT) needs further research. In this study, we investigated the signaling mechanism, which is responsible for reduced cell invasion after suppression of CYR61 in mesenchymal transformed breast cancer cells and in triple negative breast cancer cells.Methods: We addressed this issue by generating a mesenchymal transformed breast cancer cell line using prolonged mammosphere cultivation. Western blotting and quantitative PCR were used to analyze gene expression alterations. Transient gene silencing was conducted using RNA interference. Proliferation was assessed using AlamarBlue assay. Invasiveness was analyzed using 2D and 3D invasion assays. Immune-histochemical analysis of patient tissue samples was performed to examine the prognostic value of CYR61 expression.Results: In this study, we investigated whether CYR61 could be used as therapeutic target and prognostic marker for invasive breast cancer. We discovered an interaction of CYR61 with metastasis-associated protein S100A4. Suppression of CYR61 by RNA interference reduced the expression of S100A4 dependent on ERK1/2 activity regulation. Non-invasive breast cancer cells became invasive due to extracellular CYR61 supplement. Immune-histochemical analysis of 239 patient tissue samples revealed a correlation of higher CYR61 and S100A4 expression with invasive breast cancer and metastasis.Conclusion: Our data suggest that suppression of CYR61 impedes the formation of an invasive cancer cell phenotype by reducing ERK1/2 phosphorylation thereby suppressing S100A4. These findings identify mechanisms by which CYR61 suppresses cell invasion and suggest it to be a potential therapeutic target and prognostic marker for invasive breast cancer and metastasis.
Highlights
In 2019, approximately 271270 woman and men in the United States will be diagnosed with breast cancer
Mesenchymal transformed breast cancer cells show a TGFβdependent increased invasive and metastatic potential [20]. It is still under debate, if Epithelial-mesenchymal transition (EMT) programs are indispensable for cell invasion [4] and which key players are crucial for pathological EMT programs
We investigated whether within dynamic EMT programs or triple-negative breast cancer (TNBC; no expression of estrogen or progesterone and no overexpression of Her2neu) cells show changes in cysteine-rich angiogenic inducer 61 (CYR61) expression
Summary
In 2019, approximately 271270 woman and men in the United States will be diagnosed with breast cancer. The contribution of EMT programs to the metastatic cascade regarding breast cancer is supported by several publications [6,7,8]. It is still under debate if an involvement of EMT programs is indispensable for creating an invasive phenotype [4]. The cysteine-rich angiogenic inducer 61 (CYR61) is upregulated in mesenchymal transformed and invasive breast cancer cells. The signaling mechanism that causes invasive properties of cancer cells regarding to epithelial-mesenchymal transition (EMT) needs further research. We investigated the signaling mechanism, which is responsible for reduced cell invasion after suppression of CYR61 in mesenchymal transformed breast cancer cells and in triple negative breast cancer cells
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