Tumorigenic Effects of Tamoxifen on the Female Genital Tract

Nasu, Kaei; Takai, Noriyuki; Nishida, Masakazu; Narahara, Hisashi

doi:10.4137/cpath.s487

Cited by 23 publications

(23 citation statements)

References 162 publications

(319 reference statements)

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“…In fact, no changes in uterine growth were detected in two GPER1 knockout mouse models (Otto et al, 2009;Windahl et al, 2009). Despite the lack of general agreement on the impact of GPER1 selective agonists in nonvascular tissues (Prossnitz and Barton, 2014), several studies conversely point to a predominant role for ERa in estrogen and tamoxifen uterotrophic effects (Nasu et al, 2008;Bolego et al, 2010). Hence, pharmacological activation of GPER1 may be safer than estrogen-based therapeutic regimens in relation to the female genital tract.…”

Section: Discussionmentioning

confidence: 99%

The Glycolytic Enzyme PFKFB3 Is Involved in Estrogen-Mediated Angiogenesis via GPER1

Trenti

Tedesco

Boscaro

et al. 2017

J Pharmacol Exp Ther

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The endogenous estrogen 17-estradiol (E2) is a key factor in promoting endothelial healing and angiogenesis. Recently, proangiogenic signals including vascular endothelial growth factor and others have been shown to converge in endothelial cell metabolism. Because inhibition of the glycolytic enzyme activator phosphofructokinase-2/fructose-2,6-bisphosphatase 3 (PFKFB3) reduces pathologic angiogenesis and estrogen receptor (ER) signaling stimulates glucose uptake and glycolysis by inducing PFKFB3 in breast cancer, we hypothesized that E2 triggers angiogenesis in endothelial cells via rapid ER signaling that requires PFKFB3 as a downstream effector. We report that treatment with the selective G protein-coupled estrogen receptor (GPER1) agonist G-1 (10 to 10 M) mimicked the chemotactic and proangiogenic effect of E2 as measured in a number of short-term angiogenesis assays in human umbilical vein endothelial cells (HUVECs); in addition, E2 treatment upregulated PFKFB3 expression in a time- and concentration-dependent manner. Such an effect peaked at 3 hours and was also induced by G-1 and abolished by pretreatment with the GPER1 antagonist G-15 or GPER1 siRNA, consistent with engagement of membrane ER. Experiments with the PFKFB3 inhibitor 3-(3-pyridinyl)-1-(4-pyridinyl)-2-propen-1-one showed that PFKFB3 activity was required for estrogen-mediated HUVEC migration via GPER1. In conclusion, E2-induced angiogenesis was mediated at least in part by the membrane GPER1 and required upregulation of the glycolytic activator PFKFB3 in HUVECs. These findings unravel a previously unrecognized mechanism of estrogen-dependent endocrine-metabolic crosstalk in HUVECs and may have implications in angiogenesis occurring in ischemic or hypoxic tissues.

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Section: Discussionmentioning

confidence: 99%

The Glycolytic Enzyme PFKFB3 Is Involved in Estrogen-Mediated Angiogenesis via GPER1

Trenti

Tedesco

Boscaro

et al. 2017

J Pharmacol Exp Ther

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“…CYP2B1 and CYP2B2 have been shown to increase in the liver of tamoxifen (TAM)-treated Sprague Dawley rats (Nuwaysir et al, 1995). TAM exerts an estrogenic effect on the uterus in humans resulting in an increased risk of cancer in that tissue (Nasu et al, 2008). In a recent study, catechol-estrogen metabolite (4-hydroxyestrone) increased, COMT expression decreased, and expression of CYP1B1 increased in a human endometrial cell line exposed to TAM (Williams-Brown et al, 2011).…”

Section: Discussionmentioning

confidence: 99%

Disruption of estrogen homeostasis as a mechanism for uterine toxicity in Wistar Han rats treated with tetrabromobisphenol A

Sanders

Coulter

Knudsen

et al. 2016

Toxicology and Applied Pharmacology

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Chronic oral treatment of tetrabromobisphenol A (TBBPA) to female Wistar Han rats resulted in increased incidence of cell proliferation at 250 mg/kg and tumor formation in the uterus at higher doses. The present study was designed to test the hypothesis that disruption of estrogen homeostasis was a major mode-of-action for the observed effects. Biological changes were assessed in serum, liver, and the proximal (nearest the cervix) and distal (nearest the ovaries) sections of the uterine horn of Wistar Han rats 24 hours following administration of the last of five daily oral doses of 250 mg/kg. Expression of genes associated with receptors, biosynthesis, and metabolism of estrogen was altered in the liver and uterus. TBBPA treatment also resulted in changes in expression of genes associated with cell division and growth. Changes were also observed in the concentration of thyroxine in serum and in expression of genes in the liver and uterus associated with thyroid hormone receptors. Differential expression of some genes was tissue-dependent or specific to tissue location in the uterus. The biological responses observed in the present study support the hypothesis that perturbation of estrogen homeostasis is a major mode-of-action for TBBPA-mediated cell proliferation and tumorigenesis previously observed in the uterus of TBBPA-treated Wistar Han rats.

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“…Some case reports indicate that Tamoxifen provided symptomatic relief for BML patients, but very rarely did treatment cause regression of tumor nodules (23,30). (Table 1) The reports of unsuccessful results with Tamoxifen therapy can be attributed to its estrogen agonism on the myometrium (31), with one case report demonstrating the ability of Tamoxifen to promote extrauterine leiomyoma growth (32). Raloxifene, another SERM, which has a known estrogenic antagonist effect on the breast and uterus, has shown greater success in treatment of BML (33).…”

Section: Discussionmentioning

confidence: 99%

Novel hormone treatment of benign metastasizing leiomyoma: an analysis of five cases and literature review

Lewis

Chason

DeCherney

et al. 2013

Fertility and Sterility

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Objective To evaluate novel hormonal therapies in patients with unresectable Benign Metastasizing Leiomyoma (BML) disease. Design Case series. Setting National Institutes of Health (NIH). Patients 5 subjects with the diagnosis of BML based on imaging and/or histopathologic diagnosis. Interventions Four patients were treated with single or combination therapy of Leuprolide acetate and/or an aromatase inhibitor. One patient was treated with an antiprogestin (CDB-2914). Main Outcome Measures Response to therapy was measured by tumor burden on cross-sectional imaging employing RECIST (Response Evaluation Criteria in Solid Tumours) 1.1 guidelines. Results Four patients treated with single or combination therapy of Leuprolide acetate and/or an aromatase inhibitor demonstrated stable disease with reduction in tumor burden. The fifth patient treated with antiprogestin (CDB-2914) had degeneration of her tumor, progression of its size and an improvement in symptoms. Conclusions Hormonal treatment with GnRH agonism and/or aromatase inhibition may be a therapeutic option to reduce tumor burden in unresectable BML disease or for those patients who wish to avoid surgical intervention. RECIST 1.1 guidelines, while traditionally used to evaluate tumor response to cancer therapeutics, may be useful in evaluating BML tumor burden response to hormonal therapy.

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Tumorigenic Effects of Tamoxifen on the Female Genital Tract

Cited by 23 publications

References 162 publications

The Glycolytic Enzyme PFKFB3 Is Involved in Estrogen-Mediated Angiogenesis via GPER1

The Glycolytic Enzyme PFKFB3 Is Involved in Estrogen-Mediated Angiogenesis via GPER1

Disruption of estrogen homeostasis as a mechanism for uterine toxicity in Wistar Han rats treated with tetrabromobisphenol A

Novel hormone treatment of benign metastasizing leiomyoma: an analysis of five cases and literature review

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