Ventral prostate and mammary gland phenotype in mice with complete deletion of the ERβ gene

Warner, Margaret; Wu, Wenbiao; Montanholi, Leticia; Nalvarte, Ivan; Antonson, Per; Gustafsson, Jan Åke

doi:10.1073/pnas.1920478117

Cited by 28 publications

(32 citation statements)

References 44 publications

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“…Furthermore, in a very recent work, Warner et al have reevaluated the role of ERβ, using the CRISPR/Cas9 technology to create an ERβ KO mouse model in which the entire gene has been deleted. These authors observed the formation of in situ ductal cancer in the prostate and mammary gland in ERβ KO mice, and then confirming an oncosuppressive role of this receptor [20].…”

Section: Of 28mentioning

confidence: 69%

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

Sellitto

D’Agostino

Alexandrova

et al. 2020

Cancers

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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.

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Section: Of 28mentioning

confidence: 69%

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

Sellitto

D’Agostino

Alexandrova

et al. 2020

Cancers

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“…E2 is highly lipophilic and can easily pass from the periphery to the brain. In female mice older than 13 months, the reduction of oocyte follicles and the consequent decrease in blood E2 levels 46 could affect brain E2 status, that would depend mainly on brain local production, compromising E2-dependent neuroprotective mechanism 47 . The concept of an enhanced E2 signaling in the brain of Cyp46Tg females is also supported by the fact that Ers2 and Apod, an ERβ-specific target gene 48 , are increased in the hippocampus of these mice.…”

Section: Discussionmentioning

confidence: 99%

Sex-dependent effects of CYP46A1 overexpression on cognitive function during aging

Latorre-Leal

Rodriguez-Rodriguez

Franchini

et al. 2021

Preprint

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Cholesterol turnover and CYP46A1 regulation are reported to be crucial for memory functions. An increasing body of evidence shows that CYP46A1 activation is able to reduce Alzheimer’s Disease (AD) pathological processes. In this study we report for the first time that CYP46A1 overexpression and increase of 24S-hydroxycholesterol (24OH) induces sex-specific changes in synaptic functions in aged mice, being beneficial in females while detrimental in males. The positive effects on cognition in aged CYP46A1 overexpressing female mice were accompanied by morphological changes in dendritic spines and enhancement of estrogen receptor signaling in hippocampus. In aged males, CYP46A1 overexpression leads to anxiety-like behavior and worsening of spatial memory, followed by decreased dendritic spine density and higher 5α-dihydrotestosterone (DHT) levels in hippocampus. Further, analysis of cerebrospinal fluid (CSF) from AD, mild cognitive impairment and healthy patients revealed that 24OH was negatively associated to markers of neurodegeneration in women but not in men. Based on our results, CYP46A1 activation may represent a pharmacological target that could specifically enhance brain estrogen receptor signaling in women at risk of developing AD. Finally, this study highlights the importance of taking into account the sex-dimension in both preclinical and clinical studies of neurodegenerative diseases like AD.

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“…Materials. The details of a mouse line with a constitutive knockout of the ERβ gene using CRISPR-Cas9−mediated gene editing was previously reported by our group (13).…”

Section: Methodsmentioning

confidence: 97%

“…When ERβ is completely removed from the mouse genome (ERβ crispr−/− mice), there is epithelial hyperplasia, fibroplasia, and stromal overgrowth and intra ductal cancerlike lesions in the VP. These phenotypes are accompanied by an increase in P63 and Ki67, and loss of Purα and DACH1, two AR repressors (13). Thus, activating ERβ in the VP should be considered to be a target for the treatment of early-stage PCa to prevent cancer progression.…”

mentioning

confidence: 99%

Estrogen receptor β and treatment with a phytoestrogen are associated with inhibition of nuclear translocation of EGFR in the prostate

Wang

Spetsieris

et al. 2021

Proc. Natl. Acad. Sci. U.S.A.

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Knockout of ERβ in the mouse leads to nuclear expression of epidermal growth factor receptor (EGFR) in the prostate. To examine whether ERβ plays a similar role in the human prostate, we used four cohorts of men: 1) a Swedish cohort of normal prostates and PCa (prostate cancer) of different Gleason grades; 2) men with benign prostatic hyperplasia (BPH) treated with the 5α-reductase inhibitor, finasteride, and finasteride together with the ERβ agonists, soy isoflavones; 3) men with PCa above Gleason grade 4 (GG4), treated with ADT (androgen deprivation therapy) and abiraterone (AA), the blocker of androgen synthesis for different durations; and 4) men with GG4 PCa on ADT or ADT with the AR (androgen receptor) blocker, enzalutamide, for 4 mo to 6 mo. In men with BPH, finasteride treatment induced EGFR nuclear expression, but, when finasteride was combined with isoflavones, EGFR remained on the cell membrane. In GG4 patients, blocking of AR for 4 mo to 6 mo resulted in loss of ERβ and PTEN expression and increase in patients with nuclear EGFR from 10 to 40%. In the men with GG4 PCa, blocking of adrenal synthesis of testosterone for 2 mo to 7 mo had the beneficial effect of increasing ERβ expression, but, on treatment longer than 8 mo, ERβ was lost and EGFR moved to the nucleus. Since nuclear EGFR is a predictor of poor outcome in PCa, addition of ERβ agonists together with abiraterone should be considered as a treatment that might sustain expression of ERβ and offer some benefit to patients.

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Ventral prostate and mammary gland phenotype in mice with complete deletion of the ERβ gene

Cited by 28 publications

References 44 publications

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

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

Sex-dependent effects of CYP46A1 overexpression on cognitive function during aging

Estrogen receptor β and treatment with a phytoestrogen are associated with inhibition of nuclear translocation of EGFR in the prostate

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