Transcriptional regulation of tenascin‐W by TGF‐beta signaling in the bone metastatic niche of breast cancer cells

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. What's new? Once breast cancer metastasizes, it is generally incurable. Proteins in the extracellular matrix play a crucial role in launching the tumor cells to a new site. These authors investigated one such protein, tenascin‐W, which can be found surrounding not only tumor cells but also in bone tissue. Among other things, they studied how breast cancer cells affected tenascin‐W expression. The tumor cells induced bone marrow stromal cells to make more tenascin‐W, suggesting that the protein may pave the way for the cancer to spread to the bone.