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

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.

Prolactin: The Third Hormone in Breast Cancer

“…Consistent with low numbers of intratumoral lymphocytes, including CD8+ effector T cells, but large numbers of infiltrating macrophages, tumors contained strikingly reduced transcripts for many chemokines and indicators of anti-tumor immunity. This immunosuppressed environment resembles that of clinical ER+ breast cancers [reviewed in ( 67 , 68 )].…”

Tumor-derived miR-130b-3p induces cancer-associated fibroblast activation by targeting SPIN90 in luminal A breast cancer

“…Although the use of adjuvant endocrine therapy and surgery has considerably improved survival rates, 20–40% of patients develop distant metastasis. In tumor metastasis, the crosstalk between cancer cells and their microenvironment is important [ 5 , 6 ]. The tumor microenvironment (TME), which is composed of fibroblasts, immune cells, endothelial cells, and extracellular matrix (ECM), plays a pivotal role in breast cancer growth and invasion [ 7 ].…”