Syndecan-1 facilitates breast cancer metastasis to the brain

Abstract

Purpose: Although survival rates for patients with localized breast cancer have increased, patients with metastatic breast cancer still have poor prognosis. Understanding key factors involved in promoting breast cancer metastasis is imperative for better treatments. In this study, we investigated the role of syndecan-1 (Sdc1) in breast cancer metastasis. Methods:To assess the role of Sdc1 in breast cancer metastasis, we silenced Sdc1 expression in the triplenegative breast cancer human MDA-MB-231 cell line and overexpressed it in the mouse mammary carcinoma 4T1 cell line. Intracardiac injections were performed in an experimental mouse metastasis model using both cell lines. In vitro transwell blood-brain barrier (BBB) and brain section adhesion assays were utilized to specifically investigate how Sdc1 promotes brain metastasis. A cytokine array was performed to evaluate differences in the breast cancer cell secretome when Sdc1 is silenced.Results: Silencing expression of Sdc1 in breast cancer cells significantly reduced metastasis to the brain. Conversely, overexpression of Sdc1 increased metastasis to the brain. We found that silencing of Sdc1 expression had no effect on attachment of breast cancer cells to brain endothelial cells or astrocytes, but migration across the BBB was reduced as well as adhesion to the perivascular regions of the brain. Loss of Sdc1 also led to changes in breast cancer cell-secreted cytokines/chemokines, which may influence the BBB. Conclusions:Taken together, our study demonstrates a role for Sdc1 in promoting breast cancer metastasis to the brain. These findings suggest that Sdc1 supports breast cancer cell migration across the BBB through regulation of cytokines, which may modulate the BBB. Further elucidating this mechanism will allow for the development of therapeutic strategies to combat brain metastasis.

Single-cell analyses reveal a continuum of cell state and composition changes in the malignant transformation of polyps to colorectal cancer

“…Among the receptors that were most correlated with position along the malignancy continuum were the syndecan family proteins, SDC1 and SDC4 (Figure S4D). Syndecan proteins function as coreceptors for growth factors, matrix proteins, cytokines, and chemokines and have been suggested to both promote or suppress cancer (Sayyad et al, 2019). One possible mechanism by which these proteins could contribute to cancer formation is through signals from the developing tumor microenvironment.…”

Identification of Potential Key Genes Associated With the Pathogenesis, Metastasis, and Prognosis of Triple-Negative Breast Cancer on the Basis of Integrated Bioinformatics Analysis

“…Aside from the influence on the migration ability of TNBC cells, SDC1 knockdown was also found to reduce the lung metastatic burden by over 97% in a lung metastasis mouse model (30). Silencing the expression of SDC1 in TNBC cells significantly reduced metastasis to the brain, and conversely, overexpression of SDC1 increased metastasis to the brain (31). Together, these findings demonstrate the critical role of SDC1 in the proliferation, migration, and metastasis of TNBC.…”

Molecular heterogeneity in breast carcinoma cells with increased invasive capacities

“…which were detected in the metastatic lesions. 1,4,23,28 In our opinion, these pathways are the final "downstream" events in the chain of molecular perturbations resulting in metastasis development. Unfortunately, it is still not fully elucidated which molecules and pathways can be considered as initiators of metastatic cascade in breast cancer.…”

“…Syndecans are membrane proteins controlling cell proliferation, differentiation, adhesion and migration 22 and were recently shown to promote breast cancer metastasis. 23 Thus, invasiveness of T47D-INV cells may potentially be linked with activation of this pathway. Au565-INV 57.7 ± 3.5*** 6.1 ± 1.4*** * p < 0.5; *** P < 0.001…”