Alternatively spliced tissue factor synergizes with the estrogen receptor pathway in promoting breast cancer progression

Summary Background Procoagulant full‐length tissue factor (fl TF ) and its minimally coagulant alternatively spliced isoform (as TF ), promote breast cancer (BrCa) progression via different mechanisms. We previously showed that fl TF and as TF are expressed by BrCa cells, resulting in autoregulation in a cancer milieu . BrCa cells often express hormone receptors such as the estrogen receptor ( ER ), leading to the formation of hormone‐regulated cell populations. Objective To investigate whether TF isoform‐specific and ER ‐dependent pathways interact in BrCa. Methods Tissue factor isoform‐regulated gene sets were assessed using ingenuity pathway analysis. Tissues from a cohort of BrCa patients were divided into ER ‐positive and ER ‐negative groups. Associations between TF isoform levels and tumor characteristics were analyzed in these groups. BrCa cells expressing TF isoforms were assessed for proliferation, migration and in vivo growth in the presence or absence of estradiol. Results Ingenuity pathway analysis pointed to similarities between ER ‐ and TF ‐induced gene expression profiles. In BrCa tissue specimens, as TF expression was associated with grade and stage in ER ‐positive but not in ER ‐negative tumors. fl TF was only associated with grade in ER ‐positive tumors. In MCF ‐7 cells, as TF accelerated proliferation in the presence of estradiol in a β1 integrin‐dependent manner. No synergy between as TF and the ER pathway was observed in a migration assay. Estradiol accelerated the growth of as TF ‐expressing tumors but not control tumors in vivo in an orthotopic setting. Conclusion Tissue factor isoform and estrogen signaling share downstream targets in BrCa; the concomitant presence of as TF and estrogen signaling is required to promote BrCa cell proliferation.