Megan R Sayyad1, Madhavi Puchalapalli1,2, Natasha G Vergara2,3, Sierra Mosticone Wangensteen1, Melvin Moore2,3, Liang Mu2, Chevaunne Edwards2, Aubree Anderson2, Stefanie Kall2,3, Megan Sullivan2, Mikhail Dozmorov4, Jaime Singh1, Michael O Idowu1, Jennifer E Koblinski5,6,7. 1. Department of Pathology, School of Medicine, Massey Cancer Center, Virginia Commonwealth University, Richmond, VA, USA. 2. Department of Pathology, Women's Cancer Research Program, Feinberg School of Medicine, Robert H. Lurie Comprehensive Cancer Institute, Northwestern University, Chicago, IL, USA. 3. McCormick School of Engineering, Department of Chemical and Biological Engineering, Northwestern University, Evanston, IL, USA. 4. Department of Biostatistics, School of Medicine, Massey Cancer Center, Virginia Commonwealth University, Richmond, VA, USA. 5. Department of Pathology, School of Medicine, Massey Cancer Center, Virginia Commonwealth University, Richmond, VA, USA. Jennifer.koblinski@vcuhealth.org. 6. Department of Pathology, Women's Cancer Research Program, Feinberg School of Medicine, Robert H. Lurie Comprehensive Cancer Institute, Northwestern University, Chicago, IL, USA. Jennifer.koblinski@vcuhealth.org. 7. Department of Pathology, School of Medicine, Virginia Commonwealth University, Sanger Hall 4-013, 1101 E. Marshall St, Box 980662, Richmond, VA, 23298, USA. Jennifer.koblinski@vcuhealth.org.
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 triple-negative 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 facilitates 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.
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 triple-negative breast cancerhumanMDA-MB-231 cell line and overexpressed it in the mouse mammary carcinoma4T1 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 facilitates 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.
Entities:
Keywords:
Blood–brain barrier; Brain metastasis; Breast cancer; Syndecan-1