Clinical and Genomic Crosstalk between Glucocorticoid Receptor and Estrogen Receptor α In Endometrial Cancer

Vahrenkamp, Jeffery M.; Yang, Cheng‐Yu; Rodriguez, Adriana C.; Almomen, Aliyah; Berrett, Kristofer C.; Trujillo, Alexis N.; Guillen, Katrin P.; Welm, Bryan E.; Jarboe, Elke A.; Janát-Amsbury, Margit M.; Gertz, Jason

doi:10.1016/j.celrep.2018.02.076

Cited by 53 publications

(48 citation statements)

References 51 publications

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“…Indeed, blocking dynorphin action with a kappaopioid receptor antagonist elicits an increase in LH pulse frequency [23,47] which is associated with increased multi-unit activity in the mediobasal hypothalamus [23]. We evaluated dynorphin expression in animals treated with chronic corticosterone and estradiol, based on observations that ER and GR can alter transcriptional activity via crosstalk at promoter response elements [48,49], including at the dynorphin promoter leading to increased dynorphin expression [50]. However, the current study showed a decrease in dynorphin mRNA expression in response to corticosterone, suggesting that upregulation of this inhibitory peptide is not likely to underlie the suppression in LH here.…”

Section: Discussion/conclusionmentioning

confidence: 99%

Estradiol Enables Chronic Corticosterone to Inhibit Pulsatile Luteinizing Hormone Secretion and Suppress Kiss1 Neuronal Activation in Female Mice

et al. 2019

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Introduction: Two common responses to stress include elevated circulating glucocorticoids and impaired luteinizing hormone (LH) secretion. We have previously shown that a chronic stress level of corticosterone can impair ovarian cyclicity in intact mice by preventing follicular-phase endocrine events. Objective: This study is aimed at investigating if corticosterone can disrupt LH pulses and whether estradiol is necessary for this inhibition. Methods: Our approach was to measure LH pulses prior to and following the administration of chronic corticosterone or cholesterol in ovariectomized (OVX) mice treated with or without estradiol, as well as assess changes in arcuate kisspeptin (Kiss1) neuronal activation, as determined by co-expression with c-Fos. Results: In OVX mice, a chronic 48 h elevation in corticosterone did not alter the pulsatile pattern of LH. In contrast, corticosterone induced a robust suppression of pulsatile LH secretion in mice treated with estradiol. This suppression represented a decrease in pulse frequency without a change in amplitude. We show that the majority of arcuate Kiss1 neurons contain glucocorticoid receptor, revealing a potential site of corticosterone action. Although arcuate Kiss1 and Tac2 gene expression did not change in response to corticosterone, arcuate Kiss1 neuronal activation was significantly reduced by chronic corticosterone, but only in mice treated with estradiol. Conclusions: Collectively, these data demonstrate that chronic corticosterone inhibits LH pulse frequency and reduces Kiss1 neuronal activation in female mice, both in an estradiol-dependent manner. Our findings support the possibility that enhanced sensitivity to glucocorticoids, due to ovarian steroid milieu, may contribute to reproductive impairment associated with stress or pathophysiologic conditions of elevated glucocorticoids.

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Section: Discussion/conclusionmentioning

confidence: 99%

Estradiol Enables Chronic Corticosterone to Inhibit Pulsatile Luteinizing Hormone Secretion and Suppress Kiss1 Neuronal Activation in Female Mice

et al. 2019

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“…It has been mentioned that SRC‐3 as an ERα cofactor is shared between breast cancer and ECa, and it is still unknown whether endometrial cancer‐specific ERα cofactors exist 27 . A previous study described the crosstalk between the glucocorticoid receptor (GR) and ERα in ECa, demonstrating that GR genomic binding sites are reprogrammed in ECa cells following treatment with E2 and dexamethasone (Dex), in which more GR were recruited to the sites normally bound by ERα to promote ECa progression 30 . Therefore, modulation of ERα‐induced transcriptional activation would be crucial for ECa.…”

Section: Discussionmentioning

confidence: 99%

ASH2L is involved in promotion of endometrial cancer progression via upregulation of PAX2 transcription

Zeng

Wang

et al. 2020

Cancer Science

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Absent, small or homeotic 2‐like protein (ASH2L) is a core component of a multimeric histone methyltransferase complex that is involved in the maintenance of active transcription, participating in several cancers, however the biological function and molecular mechanism of ASH2L in endometrial cancer (ECa) are largely unknown. Endometrial cancer is a common malignant tumor in women and the incidence of this cancer is on the rise. Estrogen‐ERα signaling, as an oncogenic pathway, plays a crucial role in endometrial carcinogenesis. Therefore, further exploration of the molecular mechanisms around ERα‐mediated gene transcription in ECa would be helpful to the understanding of tumor development and to finding a new therapeutic target for ECa. Here, our study demonstrated that ASH2L was highly expressed in ECa samples, and higher expression of ASH2L was positively correlated with a poor prognosis. Moreover, we identified that ASH2L associated with ERα and that knockdown of ASH2L resulted in decreased expression of a subset of the estrogen‐induced target genes, including paired box 2 (PAX2), an oncogenic gene in ECa. ASH2L was recruited to cis‐regulatory elements in PAX2, thereby altering histone H3K4me3 and H3K27me3 levels, to enhance ERα‐mediated transactivation. Finally, depletion of ASH2L suppressed endometrial cancer cell proliferation and migration. Our findings suggest that ASH2L participates in the promotion of ECa progression, if not totally at least partially, via upregulation of PAX2 transcription.

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“…Even though SHR-regulated transcription was initially studied as single receptor events, mediated by SHR homodimers [35], it is becoming evident that SHR crosstalk with each other and frequently co-regulate gene expression [34]. ER/GR crosstalk was extensively studied in hormone-dependent tissues such as uterus and breast, and in hormone-dependent cancers [34,[36][37][38]. Even though there has been a perception in the literature that GR and ER effects on gene expression are frequently reciprocal, careful literature analysis revealed that GR/ ER interactions are much more complex and cell and gene context-dependent.…”

Section: Discussionmentioning

confidence: 99%

“…Even though there has been a perception in the literature that GR and ER effects on gene expression are frequently reciprocal, careful literature analysis revealed that GR/ ER interactions are much more complex and cell and gene context-dependent. Indeed, there is an extensive overlap in ER and GR chromatin binding; both hormones induce global reprogramming of chromatin landscape that affects DNA accessibly for both receptors [36,38]. Moreover, upon co-activation, increased GR chromatin binding was observed at ER response elements, and at the same time, ER was associated with GR response elements, suggesting that ER and GR interact in a complex [34,36,38].…”

Section: Discussionmentioning

confidence: 99%

Sexual dimorphism in atrophic effects of topical glucocorticoids is driven by differential regulation of atrophogene REDD1 in male and female skin

et al. 2020

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Topical glucocorticoids, well-known anti-inflammatory drugs, induce multiple adverse effects, including skin atrophy. The sex-specific effects of systemic glucocorticoids are known, but sexual dimorphism of therapeutic and side effects of topical steroids has not been studied. We report here that female and male mice were equally sensitive to the anti-inflammatory effect of glucocorticoid fluocinolone acetonide (FA) in ear edema test. At the same time, females were more sensitive to FA-induced skin atrophy. We recently reported that REDD1 (regulated in development and DNA damage 1) plays central role in steroid atrophy. We found that REDD1 was more efficiently activated by FA in females, and that REDD1 knockout significantly protected female but not male mice from skin atrophy. Studies using human keratinocytes revealed that both estradiol and FA induced REDD1 mRNA/protein expression, and cooperated when they were combined at low doses. Chromatin immunoprecipitation analysis confirmed that REDD1 is an estrogen receptor (ER) target gene with multiple estrogen response elements in its promoter. Moreover, experiments with GR and ER inhibitors suggested that REDD1 induction by these hormones was interdependent on functional activity of both receptors. Overall, our results are important for the development of safer GR-targeted therapies suited for female and male dermatological patients.

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Clinical and Genomic Crosstalk between Glucocorticoid Receptor and Estrogen Receptor α In Endometrial Cancer

Cited by 53 publications

References 51 publications

Estradiol Enables Chronic Corticosterone to Inhibit Pulsatile Luteinizing Hormone Secretion and Suppress Kiss1 Neuronal Activation in Female Mice

Estradiol Enables Chronic Corticosterone to Inhibit Pulsatile Luteinizing Hormone Secretion and Suppress Kiss1 Neuronal Activation in Female Mice

ASH2L is involved in promotion of endometrial cancer progression via upregulation of PAX2 transcription

Sexual dimorphism in atrophic effects of topical glucocorticoids is driven by differential regulation of atrophogene REDD1 in male and female skin

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