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Isoform-specific promotion of breast cancer tumorigenicity by TBX3 involves induction of angiogenesis.
Krstic, Milica; Hassan, Haider M; Kolendowski, Bart; Hague, M Nicole; Anborgh, Pieter H; Postenka, Carl O; Torchia, Joseph; Chambers, Ann F; Tuck, Alan B.
Afiliação
  • Krstic M; Department of Oncology, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada.
  • Hassan HM; The Pamela Greenaway-Kohlmeier Translational Breast Cancer Research Unit, London Regional Cancer Program, London Health Sciences Centre, London, ON, Canada.
  • Kolendowski B; Department of Pathology, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada.
  • Hague MN; Department of Oncology, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada.
  • Anborgh PH; Department of Biochemistry, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada.
  • Postenka CO; Department of Oncology, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada.
  • Torchia J; The Pamela Greenaway-Kohlmeier Translational Breast Cancer Research Unit, London Regional Cancer Program, London Health Sciences Centre, London, ON, Canada.
  • Chambers AF; Department of Biochemistry, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada.
  • Tuck AB; Mary & John Knight Translational Ovarian Cancer Research Unit, London Regional Cancer Program, London Health Sciences Centre, London, ON, Canada.
Lab Invest ; 100(3): 400-413, 2020 03.
Article em En | MEDLINE | ID: mdl-31570773
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.
Assuntos

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Neoplasias da Mama / Isoformas de Proteínas / Proteínas com Domínio T / Neovascularização Patológica Tipo de estudo: Prognostic_studies Limite: Animals / Female / Humans Idioma: En Ano de publicação: 2020 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Neoplasias da Mama / Isoformas de Proteínas / Proteínas com Domínio T / Neovascularização Patológica Tipo de estudo: Prognostic_studies Limite: Animals / Female / Humans Idioma: En Ano de publicação: 2020 Tipo de documento: Article