Background: Cancers of the reproductive system, by their very nature, occur in a sexually dimorphic manner and are influenced by exposure to reproductive hormones and dysregulated responses to sex steroids. The contributions of estrogens to the pathobiology of most breast cancers and the positive impact of endocrine therapies on outcome in this disease are well established. However, the incidence and long-term outcomes of patients with a variety of non-reproductive cancers also demonstrate sexual dimorphism (e.g. lung cancer, melanoma, glioblastoma and thyroid cancer). Whereas the mechanisms underlying these differences are complex and multifactorial, established contributing factors are gender differences in smoking, sun exposure, alcohol consumption, diet and occupational environments. Underappreciated are the contributions of sex hormones themselves to the pathobiology of non-reproductive cancers. We have determined that cancer cell extrinsic actions of estrogens/estrogen receptor-alpha (ERa) in the immune system and in the brain contribute to tumor pathology in animal models of several different cancers. Estrogens facilitate the development of an immune suppressive tumor microenvironment through direct actions on myeloid cells resulting in the attenuation of T cell activation/function. Inhibition of ER action in specific loci in the brain, however, has the paradoxical effect of increasing the growth of tumors from different tissues of origin. Understanding the cancer cell extrinsic pharmacology of ER will inform how best to use existing endocrine therapies, be instructive as to approaches to develop the next generation of modulators and enable the development of new drug combinations for the treatment of breast and gynecological cancers and other cancers originating outside of the reproductive system. Hypothesis: Maximal therapeutic efficacy of ER modulators for different cancers will be realized with the development of interventions that achieve robust inhibition of cancer cell intrinsic actions of estrogens, exhibit favorable effects on immune cell repertoire/function in tumors, and do not interfere with the homeostatic feedback mechanisms in the brain that modulate the expression of processes that impact tumor biology. Aims: (1) Define the mechanisms by which ER in tumor associated myeloid cells impacts tumor pathobiology. (2) Define the mechanism(s) by which ER expression in the brain regulates processes which impact the growth of tumors. (3) Evaluate therapeutic approaches to selectively target tumor cell extrinsic activities of ER. Impact: The effectiveness of endocrine therapies for breast cancer and other estrogen-modulated cancers has been limited by the focus on developing agents that target cancer cell intrinsic actions of ER/estrogens. By defining the mechanisms by which ER regulates immune cell function, and how it regulates hypothalamic activities that impact tumor biology in the periphery it will be possible to develop next gen...