Browsing by Subject "Estrogen Receptor alpha"

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    Defects of prostate development and reproductive system in the estrogen receptor-alpha null male mice.
    (Endocrinology, 2009-01) Chen, Ming; Hsu, Iawen; Wolfe, Andrew; Radovick, Sally; Huang, KuoHsiang; Yu, Shengqiang; Chang, Chawnshang; Messing, Edward M; Yeh, Shuyuan
    The estrogen receptor-alpha knockout (ERalphaKO, ERalpha-/-) mice were generated via the Cre-loxP system by mating floxed ERalpha mice with beta-actin (ACTB)-Cre mice. The impact of ERalpha gene deletion in the male reproductive system was investigated. The ACTB-Cre/ERalpha(-/-) male mice are infertile and have lost 90% of epididymal sperm when compared with wild-type mice. Serum testosterone levels in ACTB-Cre/ERalpha(-/-) male mice are 2-fold elevated. The ACTB-Cre/ERalpha(-/-) testes consist of atrophic and degenerating seminiferous tubules with less cellularity in the disorganized seminiferous epithelia. Furthermore, the ventral and dorsal-lateral prostates of ACTB-Cre/ERalpha(-/-) mice display reduced branching morphogenesis. Loss of ERalpha could also be responsible for the decreased fibroblast proliferation and changes in the stromal content. In addition, we found bone morphogenetic protein, a mesenchymal inhibitor of prostatic branching morphogenesis, is significantly up-regulated in the ACTB-Cre/ERalpha(-/-) prostates. Collectively, these results suggest that ERalpha is required for male fertility, acts through a paracrine mechanism to regulate prostatic branching morphogenesis, and is involved in the proliferation and differentiation of prostatic stromal compartment.
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    ERα PvuII and XbaI polymorphisms in postmenopausal women with posterior tibial tendon dysfunction: a case control study.
    (Journal of orthopaedic surgery and research, 2018-12) Pontin, PA; Nogara, PRB; Fonseca, FCP; Cesar Netto, C; Carvalho, KC; Soares Junior, JM; Baracat, EC; Fernandes, TD; Maffulli, N; Santos, MCL; Godoy-Santos, AL

    Background

    Posterior tibial tendon (PTT) insufficiency is considered as the main cause of adult acquired flat foot and is three times more frequent in females. High estrogen levels exert a positive effect on the overall collagen synthesis in tendons. We have previously demonstrated the association between some genetic single-nucleotide polymorphism (SNP) and tendinopathy. In the present study, we investigated the association of PvuII c454-397T>C (NCBI ID: rs2234693) and XbaI c454-351A>G (NCBI ID: rs9340799) SNPs in estrogen receptor alfa (ER-α) gene with PPT dysfunction.

    Methods

    A total of 92 female subjects with PTT dysfunction, with histopathological examination of the tendon and magnetic resonance image (MRI) evidence of tendinopathy, were compared to 92 asymptomatic females who presented an intact PPT at MRI for PvuII and XbaI SNPs in the ER-α gene. Genomic DNA was extracted from saliva and genotypes were obtained by polymerase chain reaction restriction fragment length polymorphism.

    Results

    The analysis of PvuII SNPs showed no significant differences in the frequency of alleles and genotypes between control and PTT dysfunction groups. The XbaI SNPs in the ER-α gene showed significant differences in the frequency of genotypes between control and test groups (p = 0.01; OR 95% 1.14 (0.55-2.33).

    Conclusions

    The XbaI SNP in the ERα gene may contribute to tendinopathy, and the A/A genotype could be a risk factor for PTT tendinopathy in this population. The PvuII SNP studied was not associated with PTT tendinopathy.
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    Inhibition of estrogen signaling in myeloid cells increases tumor immunity in melanoma.
    (The Journal of clinical investigation, 2021-12) Chakraborty, Binita; Byemerwa, Jovita; Shepherd, Jonathan; Haines, Corinne N; Baldi, Robert; Gong, Weida; Liu, Wen; Mukherjee, Debarati; Artham, Sandeep; Lim, Felicia; Bae, Yeeun; Brueckner, Olivia; Tavares, Kendall; Wardell, Suzanne E; Hanks, Brent A; Perou, Charles M; Chang, Ching-Yi; McDonnell, Donald P
    Immune checkpoint blockade (ICB) therapies have significantly prolonged patient survival across multiple tumor types, particularly in melanoma. Interestingly, sex-specific differences in response to ICB have been observed, with males receiving a greater benefit from ICB than females, although the mechanism or mechanisms underlying this difference are unknown. Mining published transcriptomic data sets, we determined that the response to ICBs is influenced by the functionality of intratumoral macrophages. This puts into context our observation that estrogens (E2) working through the estrogen receptor α (ERα) stimulated melanoma growth in murine models by skewing macrophage polarization toward an immune-suppressive state that promoted CD8+ T cell dysfunction and exhaustion and ICB resistance. This activity was not evident in mice harboring macrophage-specific depletion of ERα, confirming a direct role for estrogen signaling within myeloid cells in establishing an immunosuppressed state. Inhibition of ERα using fulvestrant, a selective estrogen receptor downregulator (SERD), decreased tumor growth, stimulated adaptive immunity, and increased the antitumor efficacy of ICBs. Further, a gene signature that determines ER activity in macrophages predicted survival in patients with melanoma treated with ICB. These results highlight the importance of E2/ER signaling as a regulator of intratumoral macrophage polarization, an activity that can be therapeutically targeted to reverse immune suppression and increase ICB efficacy.
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    Inhibition of Neu-induced mammary carcinogenesis in transgenic mice expressing ERΔ3, a dominant negative estrogen receptor α variant.
    (Hormones & cancer, 2012-12) Davis, Vicki L; Shaikh, Firdos; Gallagher, Katie M; Villegas, Michael; Rea, Sheri L; Cline, J Mark; Hughes, Claude L
    The estrogen receptor α (ERα) splicing variant with an in-frame deletion of exon 3 (ERΔ3) is frequently expressed in the normal breast, but its influence on tumorigenesis has not been explored. In vitro, ERΔ3 has dominant negative activity, suggesting it may suppress estrogen stimulation in the breast. ERΔ3 may inhibit classical signaling on estrogen response element (ERE)-regulated genes as well as activate non-classical pathways at Sp1 and AP-1 sites. Transgenic mice were developed that express mouse ERΔ3 in all tissues examined, including the mammary gland. To investigate if ERΔ3 expression affects tumorigenesis, ERΔ3 mice were crossbred with MMTV-Neu mice. Mammary tumor onset was significantly delayed in ERΔ3/Neu versus MMTV-Neu females and metastatic incidence and burden was significantly reduced. Consequently, ERΔ3 expression suppressed tumor development and metastasis in this aggressive model of HER2/Neu-positive breast cancer. To determine if ER ligands with anticancer activity may augment ERΔ3 protection, the bitransgenic mice were treated with tamoxifen and soy isoflavones starting at age 2 months. Soy protein with isoflavones (181 mg/1,800 kcal) did not affect tumor development in MMTV-Neu or ERΔ3/Neu mice; however, metastatic progression was not inhibited in soy-treated ERΔ3/Neu mice, as it was in untreated ERΔ3/Neu mice. In contrast, tamoxifen (20 mg/1,800 kcal) significantly enhanced tumor prevention in ERΔ3/Neu versus MMTV-Neu mice (98% vs. 81% tumor free). The results in ERΔ3/Neu mice demonstrate that ERΔ3 influences estrogen-dependent mammary carcinogenesis and, thus, may be protective in women expressing ERΔ3 in the breast. However, exposure to different estrogens may augment or block its beneficial effects.
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    Loss of epithelial oestrogen receptor α inhibits oestrogen-stimulated prostate proliferation and squamous metaplasia via in vivo tissue selective knockout models.
    (The Journal of pathology, 2012-01) Chen, Ming; Yeh, Chiuan-Ren; Chang, Hong-Chiang; Vitkus, Spencer; Wen, Xing-Qiao; Bhowmick, Neil A; Wolfe, Andrew; Yeh, Shuyuan
    Squamous metaplasia (SQM) is a specific phenotype in response to oestrogen in the prostate and oestrogen receptor (ER) α is required to mediate this response. Previous studies utilizing tissue recombination with seminal vesicle (SV) mesenchyme and prostatic ductal tips from wild type and ERαKO mice suggested that both epithelial and stromal ERα are necessary for SQM. However, tissue recombination is conducted in the renal capsule of immune-deficient mice, in which the microenvironment is different from normal prostate microenvironment in the intact mice. Furthermore, whether the requirement of stromal ERα in the SV for developing SQM is the same as in the prostate is unknown. Therefore, there is a clear need to evaluate the respective roles of ERα in prostate epithelial versus stromal compartments in the intact mouse. Here we generated a mouse model that has selectively lost ERα in either stromal (FSP-ERαKO) or epithelial prostate cells (pes-ERαKO) to determine the requirements of ERα for oestrogen-stimulated prostate proliferation and SQM. Our results indicated that FSP-ERαKO prostates develop full and uniform SQM, which suggests that loss of the majority (~65%) of stromal ERα will not influence oestrogen-mediated SQM. In contrast, loss of epithelial ERα inhibits oestrogen-mediated prostate growth and SQM evidenced by decreasing cytokertin 10 positive squamous cell stratification and differentiation, by reduced ERα protein expression in SQM compared to wild type mice ERα, and by the presence of normal proliferative activities in the oestrogen-treated pes-ERαKO prostates. These in vivo results suggest that epithelial ERα is required for oestrogen-mediated proliferative response and could be an appropriate target for preventing aberrant oestrogen signalling in the prostate.
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    Reduced prostate branching morphogenesis in stromal fibroblast, but not in epithelial, estrogen receptor α knockout mice.
    (Asian journal of andrology, 2012-07) Chen, Ming; Yeh, Chiuan-Ren; Shyr, Chih-Rong; Lin, Hsiu-Hsia; Da, Jun; Yeh, Shuyuan
    Early studies suggested that estrogen receptor alpha (ERα) is involved in estrogen-mediated imprinting effects in prostate development. We recently reported a more complete ERα knockout (KO) mouse model via mating β-actin Cre transgenic mice with floxed ERα mice. These ACTB-ERαKO male mice showed defects in prostatic branching morphogenesis, which demonstrates that ERα is necessary to maintain proliferative events in the prostate. However, within which prostate cell type ERα exerts those important functions remains to be elucidated. To address this, we have bred floxed ERα mice with either fibroblast-specific protein (FSP)-Cre or probasin-Cre transgenic mice to generate a mouse model that has deleted ERα gene in either stromal fibroblast (FSP-ERαKO) or epithelial (pes-ERαKO) prostate cells. We found that circulating testosterone and fertility were not altered in FSP-ERαKO and pes-ERαKO male mice. Prostates of FSP-ERαKO mice have less branching morphogenesis compared to that of wild-type littermates. Further analyses indicated that loss of stromal ERα leads to increased stromal apoptosis, reduced expression of insulin-like growth factor-1 (IGF-1) and FGF10, and increased expression of BMP4. Collectively, we have established the first in vivo prostate stromal and epithelial selective ERαKO mouse models and the results from these mice indicated that stromal fibroblast ERα plays important roles in prostatic branching morphogenesis via a paracrine fashion. Selective deletion of the ERα gene in mouse prostate epithelial cells by probasin-Cre does not affect the regular prostate development and homeostasis.