title: Transcriptional regulation of tenascin-W by TGF-beta signaling in the bone metastatic niche of breast cancer cells.
abstract: Tenascin-W is a matricellular protein with a dynamically changing expression pattern in development and disease. In adults, tenascin-W is mostly restricted to stem cell niches, and is also expressed in the stroma of solid cancers. Here, we analyzed its expression in the bone microenvironment of breast cancer metastasis. Osteoblasts were isolated from tumor-free or tumor-bearing bones of mice injected with MDA-MB231-1833 breast cancer cells. We found a fourfold upregulation of tenascin-W in the osteoblast population of tumor-bearing mice compared to healthy mice, indicating that tenascin-W is supplied by the bone metastatic niche. Transwell and co-culture studies showed that human bone marrow stromal cells (BMSCs) express tenascin-W protein after exposure to factors secreted by MDA-MB231-1833 breast cancer cells. To study tenascin-W gene regulation, we identified and analyzed the tenascin-W promoter as well as three evolutionary conserved regions in the first intron. 5'RACE analysis of mRNA from human breast cancer, glioblastoma and bone tissue showed a single tenascin-W transcript with a transcription start site at a noncoding first exon followed by exon 2 containing the ATG translation start. Site-directed mutagenesis of a SMAD4-binding element in proximity of the TATA box strongly impaired promoter activity. TGFβ1 induced tenascin-W expression in human BMSCs through activation of the TGFβ1 receptor ALK5, while glucocorticoids were inhibitory. Our experiments show that tenascin-W acts as a niche component for breast cancer metastasis to bone by supporting cell migration and cell proliferation of the cancer cells.
authors: Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland.|Faculty of Science, University of Basel, Basel, Switzerland.
authors: Francesca
authors: F
authors: Chiovaro
authors: Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland.|Faculty of Science, University of Basel, Basel, Switzerland.
authors: Enrico
authors: E
authors: Martina
authors: Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland.
authors: Alessia
authors: A
authors: Bottos
authors: Department of Biomedicine, University Hospital Basel, Basel, Switzerland.
authors: Arnaud
authors: A
authors: Scherberich
authors: Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland.|Faculty of Science, University of Basel, Basel, Switzerland.
authors: Nancy E
authors: NE
authors: Hynes
authors: Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland.|Faculty of Science, University of Basel, Basel, Switzerland.
authors: Ruth
authors: R
authors: Chiquet-Ehrismann
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology; D001859:Bone Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology* / Q000556:secondary*; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D018920:Coculture Techniques; D005260:Female; D006801:Humans; D051379:Mice; D009368:Neoplasm Transplantation; D010006:Osteoblasts / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction; D017154:Stromal Cells / Q000166:cytology / Q000378:metabolism; D019063:Tenascin / Q000235:genetics* / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D059016:Tumor Microenvironment; D015854:Up-Regulation
chemical_list: D019063:Tenascin; D016212:Transforming Growth Factor beta; C477504:tenascin-N protein, mouse; C000602572:tenascin-W, human
keywords: bone; breast cancer; gene regulation; metastatic niche; tenascin