Development of Novel Molecularly Targeted Therapy to Secreted Frizzled-Related Protein 2 for Breast Cancer
Abstract
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% of breast tumors showed intense staining for SFRP2 in the neovasculature. Importantly, SFRP2was highly expressed in the vasculature of luminal, Her2/neu, 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 SFRP2with 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. NFAT is a transcription factor that plays a critical role in mediating angiogenic responses.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jun 01, 2021
- Accession Number
- AD1202723
Entities
People
- Ann-marie Broome
- Nancy Demore
Organizations
- Medical University of South Carolina