Isoform-specific promotion of breast cancer tumorigenicity by TBX3 involves induction of angiogenesis

Abstract

TBX3 is a member of the highly conserved family of T-box transcription factors involved in embryogenesis, organogenesis and tumor progression. While the functional role of TBX3 in tumorigenesis has been widely studied, less is known about the specific functions of the different isoforms (TBX3iso1 and TBX3iso2) which differ in their DNA-binding domain. We therefore sought to investigate the functional consequence of this highly conserved splice event as it relates to TBX3-induced tumorigenesis. By utilizing a nude mouse xenograft model, we have identified differential tumorigenic potential between TBX3 isoforms, with TBX3iso1 overexpression more commonly associated with invasive carcinoma and high tumor vascularity. Transcriptional analysis of signaling pathways altered by TBX3iso1 and TBX3iso2 overexpression revealed significant differences in angiogenesis-related genes. Importantly, osteopontin (OPN), a cancer-associated secreted phosphoprotein, was significantly up-regulated with TBX3iso1 (but not TBX3iso2) overexpression. This pattern was observed across three non/weakly-tumorigenic breast cancer cell lines (21PT, 21NT, and MCF7). Up-regulation of OPN in TBX3iso1 overexpressing cells was associated with induction of hyaluronan synthase 2 (HAS2) expression and increased retention of hyaluronan in pericellular matrices. These transcriptional changes were accompanied by the ability to induce endothelial cell vascular channel formation by conditioned media in vitro, which could be inhibited through addition of an OPN neutralizing antibody. Within the TCGA breast cancer cohort, we identified an 8.1-fold higher TBX3iso1 to TBX3iso2 transcript ratio in tumors relative to control, and this ratio was positively associated with high-tumor grade and an aggressive molecular subtype. Collectively, the described changes involving TBX3iso1-dependent promotion of angiogenesis may thus serve as an adaptive mechanism within breast cancer cells, potentially explaining differences in tumor formation rates between TBX3 isoforms in vivo. This study is the first of its kind to report significant functional differences between the two TBX3 isoforms, both in vitro and in vivo.

ZFP207 sustains pluripotency by coordinating OCT4 stability, alternative splicing and RNA export

“…Most of them (eight out of ten) displayed a switching to a differentiated cell-like AS pattern upon Zfp207 knockdown, indicating that ZFP207 regulates an AS signature that controls pluripotency. In addition, several of the stem cell switches that we identified, such as Nasp or Tbx3, have been shown to be involved in cancer (Alekseev et al, 2011;Krstic et al, 2020).…”

Secreted Phosphoprotein 1 (SPP1) Promotes Angiogenesis of Glioblastoma Through Up-regulating PSMA Expression Via Transcription Factor HIF-1α

“…SPP1 also upregulates the expression of interferon-γ and interleukin-12, and is involved in Th1-mediated immunity [35,36]. Many studies revealed that SPP1 is involved in angiogenesis in tumors like breast cancer, lung cancer, melanoma and colon cancer [26,27,[37][38][39]. Despite the lack of mechanistic research, SPP1 has been highly associated with GBM angiogenesis using IHC, which consolidated our initial conclusion [40,41].…”

Heterochronic parabiosis reprograms the mouse brain transcriptome by shifting aging signatures in multiple cell types

“…TFs in common between old heterochronic and young unpaired ECs that reflect RJV included essential regulators of EC function such as Tbx3 (refs. 61 , 62 ) and Foxo4 (ref. 63 ), a member of the FOXO family of TFs that are components of a fundamental aging regulatory pathway , Patz1 , which has been implicated in regulating p53 levels and senescence in ECs 64 , and Arnt , which participates in aryl hydrocarbon receptor signaling and is involved in several aspects of vascular biology 65 (Fig.…”