Project Summary: Anti-steroid therapy is standard of care therapy for both ER+ breast cancer and for prostate cancer. Both cancers metastasize predominantly to bone. Estrogens and androgens are also key mediators of normal bone growth, homeostasis, and maintenance of the osteogenic niche in both females and males. Both cancers metastasize to the osteogenic/hematopoietic niche in trabecular bone. Accordingly, the early stage bone colonization of prostate and ER+ breast cancer may involve similar osteogenic cell-dependent mechanisms. The osteoprogenitor and osteoblasts in the osteogenic niche are regulated primarily by ERα and AR actions in both genders. Deficiencies these receptors often translate into severe pathological bone conditions. Thus, any anti-steroid therapies targeting prostate and ER+ breast cancers will also inevitably affect the microenvironment, i.e., the osteogenic niche cells. However, there is a lack of understanding of how anti- steroid therapies affect the biology of osteogenic niche cells, and how this affects cancer progression and evolution to therapeutic resistance. The Zhang and Rowley laboratories have both developed novel 3D osteogenic heterotypical organoid models that addresses human breast and prostate cancer cells interaction with human osteogenic cells respectively. Moreover, novel intra-iliac artery injection and mouse calvaria intravital imaging models have permitted the study of direct interactions with the osteogenic niche in trabecular bone in vivo. Preliminary data suggests anti-steroid therapy may result in a repair phenotype in the osteogenic niche that may promote cancer progression and therapeutic resistance. Hence, it is our hypothesis that anti- steroid therapy affects the osteogenic niche to a more homeostasis-repair phenotype that is cancer-promoting. To address this, we propose two Specific Aims. Specific Aim 1. To address bone osteogenic niche - cancer interactions in differential steroid and anti-steroid action conditions using novel 3D osteogenic organoid approaches. This Aim will address the relative importance of ERα, ERβ, and AR in mediating estrogen, androgen, and anti-steroid actions in the genesis of a reactive osteogenic niche, how it affects breast and prostate cancer biology, and how it alters anti-steroid therapeutic efficacies. Specific Aim 2. To address mechanisms of anti-steroid (estrogen and androgen) biology in the osteogenic niche and how this affects colony initiation and progression of breast and prostate cancer in vivo. Using genetically engineered mouse models, novel tumor transplantation approaches and cutting-edge intravital microscopy, we will examine the impact of anti-steroid treatments on the osteogenic niche in vivo and how it leads to endocrine resistance. The overall goal of this multi-PI proposal is to identify common mechanisms of osteogenic niche biology that affects the evolution of breast and prostate metastatic progre...