Breast Cancer Research and Treatment

, Volume 178, Issue 1, pp 35–49 | Cite as

Syndecan-1 facilitates breast cancer metastasis to the brain

  • Megan R. Sayyad
  • Madhavi Puchalapalli
  • Natasha G. Vergara
  • Sierra Mosticone Wangensteen
  • Melvin Moore
  • Liang Mu
  • Chevaunne Edwards
  • Aubree Anderson
  • Stefanie Kall
  • Megan Sullivan
  • Mikhail Dozmorov
  • Jaime Singh
  • Michael O. Idowu
  • Jennifer E. KoblinskiEmail author
Preclinical study



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.


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.


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.


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.


Breast cancer Brain metastasis Syndecan-1 Blood–brain barrier 



Blood–brain barrier





Sdc1 KD

Syndecan-1 knock-down


Non-silencing sequence

Sdc1 OE

Syndecan-1 overexpression


Empty vector


Human epidermal growth factor receptor 2 positive


Triple-negative breast cancer


Dulbecco’s modified Eagle’s medium


Fetal bovine serum


Basement membrane extract




Analysis of variance


Immortalized human umbilical vein endothelial cells


Human astrocytes


Cell index


Phosphate-buffered saline






Green fluorescent protein


Platelet endothelial cell adhesion molecule-1


Conditioned medium


Growth regulated oncogene-alpha


Intercellular adhesion molecule 1






Granulocyte colony-stimulating factor


Granulocyte-macrophage colony-stimulating factor


C–C motif chemokine ligand 5


Enzyme-linked immunosorbent assay


Tissue microarray


The cancer genome atlas



We thank Jamie Sturgill, Megan Bliss-Morrow, David Finkelstein, Emily Lanning, Kaia Schwartz, Debra Chen, Tong Zhou, and Majid Jahromi for technical assistance with experiments, Azeddine Atfi for critical review of the manuscript, and Deborah Hurtado and Nikhail Mittal (ACEA Biosciences) for their guidance with the xCELLigence System. Imaging, flow cytometry, and sequencing work were performed in part at the Northwestern University Center for Advanced Microscopy, Flow Cytometry Core, and Genomics Core generously supported by NCI CCSG P30 CA060553 awarded to the Robert H. Lurie Comprehensive Cancer Center. Services and products in support of the research project were generated by the Virginia Commonwealth University School of Nursing Biobehavioral Research Laboratory and Massey Cancer Center Flow Cytometry Shared Resource, Cancer Mouse Models Core Laboratory, and Microscopy Facility, supported, in part, with funding from NIH-NCI Cancer Center Support Grant P30 CA016059. This work was supported by the American Cancer Society RSG-123275-CSM.

Author contributions

Original idea and project development-JEK; acquisition of data-MRS, MP, NGV, SMW, MM, LM, CE, AA, SK, MS, MD, JS, MOI, JEK; analysis and interpretation of data-MRS, MP, NGV, SMW, MM, LM, CE, AA, SK, MS, MD, JS, MOI, JEK; writing-MRS, SMW, JEK. All authors have reviewed and approved this manuscript.


This work was financially supported by the American Cancer Society Research Scholar Grant ACS/RSG-123275-CSM.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

We declare that all work were performed in compliance with current U.S. laws and all animal experiments were conducted in accordance with a protocol approved by NU and VCU Institutional Animal Care and Use Committee. VCU IACUC Protocol AD10000943.

Supplementary material

10549_2019_5347_MOESM1_ESM.docx (20 kb)
Supplementary material 1 (DOCX 20 kb)
10549_2019_5347_MOESM2_ESM.pdf (2.1 mb)
Supplementary material 2 (PDF 2190 kb)


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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Megan R. Sayyad
    • 1
  • Madhavi Puchalapalli
    • 1
    • 3
  • Natasha G. Vergara
    • 3
    • 4
  • Sierra Mosticone Wangensteen
    • 1
  • Melvin Moore
    • 3
    • 4
  • Liang Mu
    • 3
  • Chevaunne Edwards
    • 3
  • Aubree Anderson
    • 3
  • Stefanie Kall
    • 3
    • 4
  • Megan Sullivan
    • 3
  • Mikhail Dozmorov
    • 2
  • Jaime Singh
    • 1
  • Michael O. Idowu
    • 1
  • Jennifer E. Koblinski
    • 1
    • 3
    • 5
    Email author
  1. 1.Department of Pathology, School of Medicine, Massey Cancer CenterVirginia Commonwealth UniversityRichmondUSA
  2. 2.Department of Biostatistics, School of Medicine, Massey Cancer CenterVirginia Commonwealth UniversityRichmondUSA
  3. 3.Department of Pathology, Women’s Cancer Research Program, Feinberg School of Medicine, Robert H. Lurie Comprehensive Cancer InstituteNorthwestern UniversityChicagoUSA
  4. 4.McCormick School of Engineering, Department of Chemical and Biological EngineeringNorthwestern UniversityEvanstonUSA
  5. 5.Department of Pathology, School of MedicineVirginia Commonwealth UniversityRichmondUSA

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