This project focuses on the problem of breast cancer metastasis and recurrence, and on a novel signaling pathway that is positioned to modulate both. The key signaling molecule is the β1 subunit of soluble guanylate cyclase (sGC), an enzyme that normally functions as a heterodimer composed of α1 and β1 subunits (termed here sGCα1 and sGCβ1). In biological models, sGCβ1, but not sGCα1, can translocate into the nucleus, where it regulates expression of p53 and specific cyclin dependent protein kinases and induces G0/G1 phase arrest. Moreover sGCβ1, but not sGCα1, markedly inhibits proliferation and colony formation of human cancer cell lines, and lengthens survival time of orthotropic implanted mice over control. In human breast cancer patients, levels of sGCβ1 (but not sGCα1) directly correlate with patient survival in authentic breast cancer patients (n =1664). The hypothesis that altered expression of sGCβ1 in tumor stroma (including epithelial cells, immune cells, and vascular endothelial cells) alters responses to niche signals and modulates breast cancer recurrence will be tested by (1) interrogating the effects of sGCβ1 expression on circulating tumor cell (CTC) cluster formation, (2) examining the role of sGCβ1 expression in modulating breast cancer recurrence arising from angiogenic dormancy, and (3) determining the ability of sGCβ1-targeted histone deacetylase signaling to reverse immune dysfunction. Successfully completed, this project will validate the importance of sGCβ1-targeted HDAC signaling against recurrence of dormant breast cancer, and point the field toward new therapeutic strategies for treating metastatic breast cancer.