Natural and Synthetic Estrogens in Chronic Inflammation and Breast Cancer

Abstract

The oncogenic role of estrogen receptor (ER) signaling in breast cancer has long been established. Interaction of estrogen with estrogen receptor (ER) in the nucleus activates genomic pathways of estrogen signaling. In contrast, estrogen interaction with the cell membrane-bound G-protein-coupled estrogen receptor (GPER) activates the rapid receptor-mediated signaling transduction cascades. Aberrant estrogen signaling enhances mammary epithelial cell proliferation, survival, and angiogenesis, hence is an important step towards breast cancer initiation and progression. Meanwhile, a growing number of studies also provide evidence for estrogen's pro- or anti-inflammatory roles. As other articles in this issue cover classic ER and GPER signaling mediated by estrogen, this review will discuss the crucial mechanisms by which estrogen signaling influences chronic inflammation and how that is involved in breast cancer. Xenoestrogens acquired from plant diet or exposure to industrial products constantly interact with and alter innate estrogen signaling at various levels. As such, they can modulate chronic inflammation and breast cancer development. Natural xenoestrogens generally have anti-inflammatory properties, which is consistent with their chemoprotective role in breast cancer. In contrast, synthetic xenoestrogens are proinflammatory and carcinogenic compounds that can increase the risk of breast cancer. This article also highlights important xenoestrogens with a particular focus on their role in inflammation and breast cancer. Improved understanding of the complex relationship between estrogens, inflammation, and breast cancer will guide clinical research on agents that could advance breast cancer prevention and therapy.

Keywords: breast cancer; chronic inflammation; environmental estrogens; natural estrogens; synthetic estrogens; xenoestrogens.

Figure 1

Schematic representation of estrogen signaling and downstream pathways regulating chronic inflammation and breast cancer etiology. Estrogen drives luminal epithelial cell transformation leading to breast cancer development via genomic, nongenomic, and mitochondrial signaling pathways. Besides promoting cell survival, proliferation, angiogenesis, and metastasis, these pathways can also modulate inflammation, innate and adaptive immunity by upregulating or activating proinflammatory mediators such as reactive oxygen species (ROS) and cyclooxygenase 2 (COX-2). Estrogen-induced chronic inflammation is an important co-conspirator in breast cancer development and progression. The anti-inflammatory function of ER signaling is also documented in pathophysiology but not discussed here. Key abbreviations: VEGF, vascular endothelial growth factor; MAPK, mitogen-activated protein kinase; Mn-SOD, Manganese superoxide dismutase; NF-κB, nuclear factor-kappa B; AP-1, activator protein-1; IL, interleukin; TNF-α, tumor necrosis factor-alpha.

Figure 2

Schematic depiction of the tumor microenvironment of breast cancer. Tumor cells, infiltrated immune cells, and adipocytes are highlighted in this schematic graph. Estrogens drive tumor cell proliferation and metastasis via transcriptional activation of cyclin Ds, anti-apoptotic factors, SRC-1, and PELP1. Estrogens also promote angiogenesis via VEGF and PDGF. Cytokines such as TNFα, IL-6, andIL-1β and inflammatory components are released mainly by infiltrated immune cells. They increase the activity of aromatase and thus elevate the estrogen level, and they also directly impact the growth of tumor cells via receptors. Estrogens elevate chemoattractant levels and thus facilitate the infiltration of MDSC, neutrophil and macrophage which then promote tumor growth. Adipocytes secrete inflammatory factors and leptin, which stimulate T cells and macrophages to produce more cytokines, forming a positive feedback, while adiponectin can inhibit immune cells.

Figure 3

Inflammatory mechanisms differentially regulated by phytoestrogens and synthetic xenoestrogens. Phytoestrogens promote anti-inflammatory responses in mammary tissue via inhibition of NF-κβ and AP-1, reduction of reactive oxygen species (ROS) in a manganese superoxide dismutase (MnSOD)-dependent manner, inhibition of COX-2, and reduced secretion of proinflammatory cytokines from innate and adaptive immune cells. On the other hand, synthetic xenoestrogens generally induce proinflammatory responses by activating NF-κβ signaling, increasing ROS generation, and enhancing the proinflammatory cytokine release from immune cells. Such responses can propagate chronic inflammation leading to breast cancer development.