ERβ-mediated induction of cystatins results in suppression of TGFβ signaling and inhibition of triple-negative breast cancer metastasis

Reese, Jordan; Bruinsma, Elizabeth S.; Nelson, Adam W; Chernukhin, Igor; Carroll, Jason S.; Liu, Ying; Subramaniam, Malayannan; Suman, Vera J.; Negron, Vivian; Monroe, David G.; Ingle, James N.; Goetz, Matthew P.; Hawse, John R.

doi:10.1073/pnas.1807751115

Cited by 49 publications

(51 citation statements)

References 46 publications

(48 reference statements)

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“…Future studies should also be performed to determine if cell-type specific signaling through ERα in the liver and/or hypothalamus underlies the metabolic and lifespan-extending effects of 17α-E2. ChIP-Sequencing and RNA-Sequencing: U2OS-ERα cells were harvested 24 hours post-treatment and chromatin immunoprecipitation was performed as previously described [106,107]. Briefly, ERα was immunoprecipitated overnight at 4ºC using 10 µg of Flag antibody (clone M2, Sigma-Aldrich, St. Louis, MO).…”

Section: Discussionmentioning

confidence: 99%

Health benefits attributed to 17α-estradiol, a lifespan-extending compound, are mediated through estrogen receptor α

Mann

Hadad

Nelson-Holte

et al. 2020

Preprint

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Aging is the greatest risk factor for most chronic diseases. Metabolic dysfunction underlies several chronic diseases, which are further exacerbated by obesity. Dietary interventions can reverse metabolic declines and slow aging processes, although compliance issues remain paramount due to adverse effects on quality of life.17α-estradiol treatment improves metabolic parameters and slows aging in male mice. The mechanism by which 17α-E2 elicits benefits remain unknown, which has led speculation that an uncharacterized receptor is involved. Herein, we show that 17α-estradiol and 17β-estradiol elicit similar genomic binding and transcriptional activation of ERα and that the ablation of ERα in male mice completely attenuates the beneficial effects of 17α-estradiol. Our findings also suggest that 17α-E2 acts primarily through the liver and/or hypothalamus to elicit benefits, and that 17α-E2 also improves metabolic parameters in male rats. Collectively, these data suggest ERα is a relevant drug target for mitigating chronic diseases in male mammals. KEYWORDS17α-estradiol, aging, estrogen receptor, hypothalamus, liver, metabolism, obesity Aging is the leading risk factor for most chronic diseases, many of which are associated with declines in metabolic homeostasis [1]. Metabolic detriments associated with advancing age are further exacerbated by obesity [2,3], which has risen substantially in the older population (> 65 years) over the past several decades [4,5]. Moreover, obesity in mid-life has been shown to accelerate aging mechanisms and induce phenotypes more commonly observed in older mammals [6][7][8][9][10][11][12]. These observations have led many to postulate that obesity may represent a mild progeria syndrome [13][14][15][16][17]. Although it is well established that dietary interventions, including calorie restriction, can reverse obesity-related metabolic sequelae, many of these strategies are not well tolerated in older patients due to concomitant comorbidities [2,18]. Compliance issues across all age groups also remain a paramount hurdle due to calorie restriction adversely affecting mood, thermoregulation, and musculoskeletal mass [19]. These adverse health outcomes demonstrate the need for pharmacological approaches aimed at curtailing metabolic perturbations associated with obesity and aging.17α-estradiol (17α-E2) is one of the more recently studied compounds to demonstrate efficacy for beneficially modulating obesity-and age-related health outcomes. The NIA Interventions Testing Program (ITP) found that long-term administration of 17α-E2 extends median lifespan of male mice in a dose-dependent manner [20,21]. Our group has been exploring potential mechanisms by which 17α-E2 may improve healthspan and extend lifespan in a sex-specific manner. We have found that 17α-E2 administration reduces food intake and regional adiposity in combination with significant improvements in a multitude of systemic metabolic parameters in both middle-aged obese and old male mice without inducing deleterious effects [22][23...

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Section: Discussionmentioning

confidence: 99%

Health benefits attributed to 17α-estradiol, a lifespan-extending compound, are mediated through estrogen receptor α

Mann

Hadad

Nelson-Holte

et al. 2020

Preprint

Self Cite

View full text Add to dashboard Cite

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“…ERβ elicites tumor-suppressive effects, particularly with regard to suppression of metastatic phenotypes, which is characterized by the induction of a family of secreted proteins known as cystatins and the subsequent inhibition of canonical transforming growth factor (TGF-β) signaling [89], leading to decreased expression of a network of genes related to extracellular matrix, cell invasion and vitamin D3 metabolism [90]. There is evidence that ERβ is involved in angiogenesis in breast cancer.…”

Section: Roles Of Erβ In Breast Cancer Cell Migration and Invasionmentioning

confidence: 99%

The role of estrogen receptor beta in breast cancer

Zhou

Liu

2020

Biomark Res

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Breast cancer, a malignant tumor originating from mammary epithelial tissue, is the most common cancer among women worldwide. Challenges facing the diagnosis and treatment of breast cancer necessitate the search for new mechanisms and drugs to improve outcomes. Estrogen receptor (ER) is considered to be important for determining the diagnosis and treatment strategy. The discovery of the second estrogen receptor, ERβ, provides an opportunity to understand estrogen action. The emergence of ERβ can be traced back to 1996. Over the past 20 years, an increasing body of evidence has implicated the vital effect of ERβ in breast cancer. Although there is controversy among scholars, ERβ is generally thought to have antiproliferative effects in disease progression. This review summarizes available evidence regarding the involvement of ERβ in the clinical treatment and prognosis of breast cancer and describes signaling pathways associated with ERβ. We hope to highlight the potential of ERβ as a therapeutic target.

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“…The attenuation of AP-1 and Sp1 mediated estradiol induced transcriptional activation is a potential, although not clearly established, mechanism for inhibition (132) and the AF1 domain of ERβ is necessary for this effect (133,134). In regard to TNBC, Reese et al suggested that ERβ induced the up-regulation of secreted proteins known as cystatins that down-regulate canonical TGFβ signaling, is critical for the suppression of the metastatic phenotype (135).…”

Section: Erβ Expression and Role In Various Cancer Typesmentioning

confidence: 99%

Estrogen Receptor Beta (ERβ): A Ligand Activated Tumor Suppressor

et al. 2020

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Estrogen receptor alpha (ERα) and estrogen receptor beta (ERβ) belong to a superfamily of nuclear receptors called steroid hormone receptors, which, upon binding ligand, dimerize and translocate to the nucleus where they activate or repress the transcription of a large number of genes, thus modulating critical physiologic processes. ERβ has multiple isoforms that show differing association with prognosis. Expression levels of the full length ERβ1 isoform are often lower in aggressive cancers as compared to normal tissue. High ERβ1 expression is associated with improved overall survival in women with breast cancer. The promise of ERβ activation, as a potential targeted therapy, is based on concurrent activation of multiple tumor suppressor pathways with few side effects compared to chemotherapy. Thus, ERβ is a nuclear receptor with broad-spectrum tumor suppressor activity, which could serve as a potential treatment target in a variety of human cancers including breast cancer. Further development of highly selective agonists that lack ERα agonist activity, will be necessary to fully harness the potential of ERβ.

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ERβ-mediated induction of cystatins results in suppression of TGFβ signaling and inhibition of triple-negative breast cancer metastasis

Cited by 49 publications

References 46 publications

Health benefits attributed to 17α-estradiol, a lifespan-extending compound, are mediated through estrogen receptor α

Health benefits attributed to 17α-estradiol, a lifespan-extending compound, are mediated through estrogen receptor α

The role of estrogen receptor beta in breast cancer

Estrogen Receptor Beta (ERβ): A Ligand Activated Tumor Suppressor

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