Insights into the Role of Estrogen Receptor β in Triple-Negative Breast Cancer

Abstract

Estrogen receptors (ERα and ERβ) are ligand-activated transcription factors that play different roles in gene regulation and show both overlapping and specific tissue distribution patterns. ERβ, contrary to the oncogenic ERα, has been shown to act as an oncosuppressor in several instances. However, while the tumor-promoting actions of ERα are well-known, the exact role of ERβ in carcinogenesis and tumor progression is not yet fully understood. Indeed, to date, highly variable and even opposite effects have been ascribed to ERβ in cancer, including for example both proliferative and growth-inhibitory actions. Recently ERβ has been proposed as a potential target for cancer therapy, since it is expressed in a variety of breast cancers (BCs), including triple-negative ones (TNBCs). Because of the dependence of TNBCs on active cellular signaling, numerous studies have attempted to unravel the mechanism(s) behind ERβ-regulated gene expression programs but the scenario has not been fully revealed. We comprehensively reviewed the current state of knowledge concerning ERβ role in TNBC biology, focusing on the different signaling pathways and cellular processes regulated by this transcription factor, as they could be useful in identifying new diagnostic and therapeutic approaches for TNBC.

Perspectives on Triple-Negative Breast Cancer: Current Treatment Strategies, Unmet Needs, and Potential Targets for Future Therapies

“…As a known tumor suppressor, persistent ERβ expression is associated with a less aggressive and non-invasive phenotype, and prolonged patient survival [ 249 ]. ERβ expression is retained in 30% of TNBCs, whereas its expression is lost in 70% of TNBC [ 250 , 251 ]. For ERβ-positive TNBC cells, adding estrogen (E2) or other ERβ-selective agonists to activate ERβ receptor can elicit potent anticancer effects by inducing cystatin gene expression, decreasing cell proliferation, inhibiting canonical TGFβ pathway activation, blocking epithelial-to-mesenchymal transition, and preventing malignant cell invasion and metastatic spread [ 252 , 253 , 254 , 255 , 256 , 257 ].…”

Carcinogenesis of Triple-Negative Breast Cancer and Sex Steroid Hormones

“…Although TNBC is defined as negative for both ER-α and PgR, some TNBC express other sex steroid hormone receptors: AR [ 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 ], ER-β [ 27 , 28 , 29 , 30 , 31 , 32 ], or GPER [ 33 , 34 , 35 , 36 , 37 , 38 ]. AR and ER-β belong to the ER type subgroup of the nuclear receptor superfamily, and typically transmit genomic signaling; however, the existence of non-genomic signaling pathways through these receptors or non-nuclear receptors located in the cytoplasmic membrane or cytoplasm has been reported and attracted attention.…”

“…Hormone (estrogen) unresponsiveness is considered the fundamental characteristic of TNBC; however, studies have revealed the expression of some sex steroid hormone receptors other than classic ER (now renamed ER-α) in TNBC; that is, androgen receptor (AR) [ 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 ], second ER (namely ER-β) [ 27 , 28 , 29 , 30 , 31 , 32 ], or non-nuclear receptors represented by G-protein-coupled estrogen receptor (GPER) [ 33 , 34 , 35 , 36 , 37 , 38 ]; suggesting the biological and/or clinical relevance of sex steroid hormones in TNBC. Physiologically present androgens and estrogens are made of cholesterol, and commonly have a steroidal structure [ 39 , 40 , 41 ].…”

“…Physiologically present androgens and estrogens are made of cholesterol, and commonly have a steroidal structure [ 39 , 40 , 41 ]. Further, the action of these hormones is exerted through similar mechanisms, not only involving nuclear transcription but also crosstalk with various intracytoplasmic pathways [ 12 , 29 , 33 , 34 ]. Physiologically, androgens and estrogens are present in the body, with various rates among organs or individuals.…”

Bisphenols and Risk of Breast Cancer: A Narrative Review of the Impact of Diet and Bioactive Food Components

“…The MCF-7 cell line has been shown to express both ERα and ERβ (26). Although ERβ has been suggested as a cancer therapeutic target (27), some studies (28) show that when ERα/β positive MCF-7 cells are treated with an active metabolite of BPA [4-methyl-2,4-bis(4-hydroxyphenyl)pent-1-ene (MBP)] at levels (∼1 nM) comparable to human environmental exposure, ERα protein expression is downregulated and proliferation is increased via ERβ. In particular, the MCF-7 proliferation stimulated by MBP is dose-dependently counteracted by the cotreatment with the selective ERβ antagonist PHTPP (4-[2phenyl-5,7-bis (trifluoromethyl) pyrazolo [1,5-a]-pyrimidin-3yl] phenol).…”