Breast cancer is the second leading cause of cancer-related deaths in the United States. The Cancer Genome Atlas (TCGA) network has classified breast cancer into four main subtypes: luminal A, luminal B, HER2+, and Triple- negative breast cancer (TNBC). TNBC constitutes 10-20% of all breast cancer and has a higher rate of distal recurrence and a poorer prognosis than other breast cancer subtypes. Less than 30% of women with metastatic TNBC survive 5 years and almost all die from their disease despite adjuvant chemotherapy. Although all of the cancer genome-sequencing efforts, there is still an incomplete understanding of the genes and genetic networks driving TNBC. To better understand the genetic forces involved in TNBC, we performed a transposon mutagenesis screen in Pten mutant mice that identified several candidate trunk drivers and a much larger number of progression genes. A major finding of our screen was the discovery and functional validation of TRPS1 as a metastasis tumor suppressor in human TNBC. Consistent with these results, in SB-Pten tumors, Trsp1 was insertionally mutated only in TNBC. Remarkably, tumor cells from ER+ breast cancer patients after antihormone therapy have decreased TRPS1 expression and increased expression of mesenchymal markers, suggesting that breast tumors with low TRPS1 expression might be more resistant to chemotherapy and have a higher probability to metastasize. TRPS1 is a GATA-like transcription factor, which functions as a transcriptional repressor or activator, depending on cell type, stage of development, or pathological conditions. Based on this assumption, we explored additional roles of TRPS1 in tumor progression. ChIP-seq array studies indicated that TRPS1 modulates the expression of genes involved in the angiogenesis pathway. To validate the functional role of TRPS1 in angiogenesis, we perform tube formation and sprouting assays using MDA-MB-231 cells overexpressing TRPS1-ORF and inactivation of TRPS1 expression in HCC70 cells by different shRNAs. Interestingly, inactivation of TRPS1 expression accelerates tube formation structures compared to the vector control as well as cell branching in the sprouting assay. Overexpression of TRPS1 prevents tubing and branching formation in vitro assays. Moreover, immunohistochemistry staining of CD31 detected a reduced number of blood vessels in MDA-MB-231 tumor xenografts overexpressing TRPS1, and an increase of angiogenic vasculature in HCC70 TRPS1-shRNA tumor xenografts. In vitro and in vivo assays demonstrate the role of TRPS1 in tumor angiogenesis and ChIP-seq data suggest a direct interaction in the modulation of genes involved in pathological neovaculature mechanisms.
Citation Format: Liliana Guzman, Jessica Bronstad, Roberto Rangel, Roberto R Rosato, Wei Qian, Jianying Zhou, Jenny C Chang. Trps1 disrupts angiogenesis in triple negative breast cancer by down regulating genes involved in angiogenesis pathways [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS17-30.