Endogenous and Therapeutic Estrogens: Maestro Conductors of the Microenvironment of ER+ Breast Cancers

SIMPLE SUMMARY: Breast cancers that express estrogen receptor alpha (ER+) are the most common subtype of breast cancers. Although surgery and anti-estrogen therapies are successful for most of these patients, treatment-resistant ER+ metastatic cancers account for the majority of breast-cancer-related deaths. Immunotherapies have shown promise for other cancer types, but these have been much less effective for ER+ breast cancers. In this review, we update progress in our understanding of the immune microenvironment and the community of other cells that surround ER+ cancer cells at the primary and metastatic sites, the responses of these different cell types to various anti-estrogen therapies, and the net outcomes in experimental and clinical studies. We highlight evolving technologies that will provide greater insight into the biology of ER+ breast cancer and the foundation for new treatment and prevention strategies, in order to reduce mortality of this disease. ABSTRACT: Estrogen receptor alpha (ERα) marks heterogeneous breast cancers which display a repertoire of somatic genomic mutations and an immune environment that differs from other breast cancer subtypes. These cancers also exhibit distinct biological behaviors; despite an overall better prognosis than HER2+ or triple negative breast cancers, disseminated dormant cells can lead to disease recurrence decades after the initial diagnosis and treatment. Estrogen is the best studied driver of these cancers, and antagonism or reduction of estrogen activity is the cornerstone of therapeutic approaches. In addition to reducing proliferation of ERα+ cancer cells, these treatments also alter signals to multiple other target cells in the environment, including immune cell subpopulations, cancer-associated fibroblasts, and endothelial cells via several distinct estrogen receptors. In this review, we update progress in our understanding of the stromal cells populating the microenvironments of primary and metastatic ER+ tumors, the effects of estrogen on tumor and stromal cells to modulate immune activity and the extracellular matrix, and net outcomes in experimental and clinical studies. We highlight new approaches that will illuminate the unique biology of these cancers, provide the foundation for developing new treatment and prevention strategies, and reduce mortality of this disease.