Development of Novel Molecularly Targeted Therapy to Secreted Frizzled-Related Protein 2 for Breast Cancer
Technical Report,01 Mar 2018,28 Feb 2019
Medical University of South Carolina Charleston United States
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Most antiangiogenic drugs evaluated in breast cancer clinical trials inhibit angiogenesis by targeting the VEGF pathway. VEGF is a driver of tumor angiogenesis in breast cancer, however modest or negative phase III clinical results suggest further targets, pathways, or factors play a significant role. Furstenburger et al. evaluated VEGF expression in primary breast cancers from patients and adjacent normal breast tissue and found no increase in VEGF levels. We hypothesized that pro-angiogenesis factors other than VEGF are drivers of human breast cancer angiogenesis. To identify these proangiogenesis factors, we developed a novel method of immuno-laser capture microdissection coupled with RNA amplification and genome-wide gene expression to profile tumor vasculature cells from human breast tumors with comparison to normal breast samples. In our analysis we identified that secreted frizzle-related protein 2 SFRP2 mRNA levels were increased more than 6-fold in breast cancer endothelium compared to normal vessels from benign breast tissue, and as shown by immunohistochemistry 85 percent of breast tumors showed intense staining for SFRP2 in the neovasculature. Importantly, SFRP2 was highly expressed in the vasculature of luminal, Her2neu, and basal tumors. Interestingly, VEGF was expressed at the same level in both tumor and benign endothelium, suggesting again that VEGF might not be a major driver of breast tumor angiogenesis. We subsequently showed that SFRP2 induces angiogenesis in vitro and in vivo, and that antagonism of SFRP2 with a monoclonal antibody inhibits triple negative breast carcinoma and angiosarcoma growth in mice. We further identified that the angiogenic activity of SFRP2 is mediated by activating the non-canonical Wnt calcineurin nuclear factor of activated T-cells c3 NFATc3 pathway. .
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