Abstract
Simple SummaryBreast 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.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.
Highlights
Breast cancer is one of the deadliest cancers, and is the second leading cause of cancerrelated deaths for women worldwide [1]
ERα marks heterogeneous clinical breast cancers which display a repertoire of somatic genomic mutations and immune environments that differ from other breast cancer subtypes
These cancers exhibit distinct biological behaviors; despite an overall better prognosis than HER2+ or triple negative breast cancers (TNBC), disseminated dormant cells can lead to disease recurrence decades after the initial diagnosis and treatment
Summary
Breast cancer is one of the deadliest cancers, and is the second leading cause of cancerrelated deaths for women worldwide [1]. Luminal B tumors displayed distinct T cell-evasive mechanisms from TNBC tumors, with higher frequencies of immunosuppressive immune populations, such as Tregs and M2-polarized macrophages (see below), rather than expression of coinhibitory receptors and ligands, such as checkpoint inhibitors, to suppress T cellmediated anti-immune responses. ER+ metastases that have acquired mutations in the ligand-binding domain of ERα (mESR1) leading to constitutive activation, most commonly in response to treatment with aromatase inhibitors, exhibited differences in the immune cell complement from metastases expressing wildtype ERα, including increased Tregs and PD-L1-expressing macrophages, and increased activity of the Type 1 IFN pathway [107] The extent of these changes suggested that acquisition of these mutations is associated with multiple compensatory pathways, apart from direct gene targets of ERα. A recent study suggested the intriguing possibility that a T cell subset may mediate tumor dormancy [112]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
