Assistant Professor, Pathology; Feinberg School of Medicine
Tumor Invasion, Metastasis & Angiogenesis,Women's Cancer
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As many as 20% of breast cancer patients have brain metastases, with women surviving only 2-16 months after diagnosis of this metastasis. Thus, resolving the mechanisms of metastasis to the brain is clinically important. In invasive breast carcinomas, Syndecan (Sdc) 1 is observed in stromal fibroblasts and endothelial cells where it is involved in tumor growth and angiogenesis. Staining for Sdc1 in both the tumor and stromal cells has been reported to be a negative predictor of disease free and overall survival in estrogen receptor (ER) negative breast tumors, and expression of Sdc1 and 4 is associated with increased proliferation index in breast tumors. A direct connection between these receptors and breast cancer metastasis has not been shown. The reduced expression of Sdc1 or 4 in MDA-231 breast cancer cells and reduced expression of Sdc4 in CN34Brm breast cancer cells significantly decreased metastases to only the brain but had no effect on bone, lung, or ovarian metastases when the cells were injected into the left ventricle of the mouse heart (nude mice). Additionally, metastases to the brain was reduced when these cells were injected in the orthotopic site of NSG mice, however, primary tumor growth and metastases to the lung, liver, ovaries, and lymph nodes were not affected in this model. These results suggest Sdc1 and 4 facilitate breast cancer organotropism to the brain. There was no difference in proliferation rate of these cells in vitro. Furthermore, intracranial injection of MDA-231 breast cancer cells with decreased expression of Sdc1 had no effect on growth within the brain. However, migration of MDA-231 through an in vitro blood brain barrier (BBB) is decreased by the knockdown of Sdc1 or 4 in these cells. These results suggest that Sdc1 and 4 may play a role in the arrival of breast cancer cells to the brain but not growth within the brain. The attachment of breast cancer cells to brain slices has been shown to be correlated with their ability to bind to the brain blood vessels after crossing the BBB and to grow in the peri-vascular space. We found that silencing of Sdc1 decreased attachment of MDA-231 cells to brain slices. Wild-type mouse Sdc1 could rescue this decrease but a mutant mouse Sdc1 lacking the whole cytoplasmic tail could not rescue the attachment. Taken together these data support the hypothesis that Sdc signaling is important in breast cancer metastasis to the brain and/or peri-vascular growth in the brain. These results suggest that movement across the BBB, attachment to the brain matrix and movement into the brain parenchyma is altered by Sdc expression. Additionally, the signaling of Sdc is important in this attachment. We are currently examining the signaling molecules that may be involved. These results may explain the correlative observations of Sdc expression with poor clinical outcome. These studies may lead to development of new biomarkers and/or treatment for breast cancer metastasis to the brain.