Abstract 3842: ZNF217 promotes breast tumor progression by facilitating angiogenesis

Abstract The transcription factor ZNF217 is amplified in 20-30% of breast cancers and is identified as a putative oncogene. Its overexpression accelerates tumor progression, metastasis, and chemoresistance in vivo and correlates strongly with poor prognosis in patients. To identify growth factors that are released from mammary epithelial cells that overexpress ZNF217, we analyzed the conditioned media from MCF7 cells with or without knockdown of ZNF217 using a 71-Plex Discovery assay. Conditioned media from MCF7 cells deficient for ZNF217 showed a significant downregulation in the secretion of VEGF-A, PDGF-AA, and PDGF-AB/BB and was validated by ELISA in conditioned media from both MCF7 cells and in MDA-MB-231 cells that overexpress ZNF217. VEGF-A, PDGF-AA, and PDGF-AB/BB are key components in promoting angiogenesis, a key hallmark of cancer. RNA sequencing data and qRT-PCR revealed no significant difference in the transcriptional expression of VEGF-A and PDGF-AA/AB/BB after ZNF217 knockdown. To evaluate if the secretion of the identified angiogenic factors promotes endothelial cell sprouting, we co-cultured endothelial progenitor cells with the conditioned media from MCF7 cells ± siZNF217. Endothelial cells treated with media from MCF7 ± siZNF217 induced a sprouting phenotype in endothelial cells grown in conditioned media from ZNF217 expressing cells compared to knockdown cells. Together, these data suggests that ZNF217 is a promotor of VEGF-A secretion and promotion of angiogenic phenotypes in endothelial cells. We also evaluated the role of ZNF217 in the expression of the VEGFR-2 signaling. Knockdown of ZNF217 also decreased the expression of KDR (VEGFR-2 receptor for VEGF-A) in MCF7 cells, suggesting a potential autocrine signaling role for VEGF-A in the cancer cells. Single cell RNA sequencing data of mammary tumors derived from orthotopic injection of PyMT±Zfp217 revealed an increased population of endothelial cells in FVB mice injected with Zfp217 overexpressing cells compared to vector expressing control cells. These findings highlight a novel role for ZNF217 as a promoter of angiogenesis during breast cancer progression. Thus, unravelling the mechanisms of ZNF217-mediated angiogenesis will be an instrumental step in determining if anti-angiogenic therapies are an effective and novel strategy used to overcome metastatic growth in breast cancer patients with tumors that overexpress ZNF217. Citation Format: Ann Dharshika Shangaradas, Parinda Tennakoon, Margaret A. Schwarz, Laurie E. Littlepage. ZNF217 promotes breast tumor progression by facilitating angiogenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3842.