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ENDO 2021

RAI Treatment of Adults with Hyperthyroidism is Safe with Regards to Cancer Risk

technical paper

Meet the Scientist: Examining the Chromatin Landscape - Epigenetic Enzymes and Transcriptional Heterogeneity

This House Believes that Following MEN1 Surveillance Guidelines Can Do More Harm than Good

Lipid Management in Patients with Endocrine Disorders: An Endocrine Society Clinical Practice Guideline

Endocrine Society Business Meeting

Steroid Receptor Co-Activators Regulate Metabolic Kinases to Drive Therapy Resistant ER+ Breast Cancer

Hormonal regulation of Semaphorin 7a promotes therapeutic resistance in breast cancer
Background: The majority of all breast cancers (BC) are estrogen receptor positive (ER+). While ER-targeting endocrine therapies have improved patient survival, many of these tumors develop drug resistance and recur within 20 years. Therefore, novel targets are needed to predict for recurrence and to treat recurrent ER+BC. Previous reports describe a tumor-promotional role for Semaphorin 7A (SEMA7A) in ER- disease; yet, the role of SEMA7A in ER+ disease is poorly characterized. Hypothesis: SEMA7A promotes cell survival and drug resistance in ER+ BC. Methods: We overexpressed SEMA7A in ER+ BC cells, then used the ER-targeting agents tamoxifen and fulvestrant to test how SEMA7A-expressing cells respond to endocrine therapy. In vitro, we used proliferation and cell survival assays. In vivo, we implanted ER+ BC cells, then treated the animals with fulvestrant to measure how SEMA7A affects tumor growth and metastasis. We also utilized drug resistant cells, which have high endogenous SEMA7A levels, to measure markers of stemness and multi-drug resistance via flow cytometry. Results: We first found that SEMA7A expression correlates with decreased relapse free survival in patients with ER+BC who received endocrine therapy (Kmplotter; p=0.042). We also observe that SEMA7A is hormonally regulated in ER+BC, but its expression does not uniformly decrease with endocrine therapy agents. Instead, long term estrogen deprivation and ER-targeting drug treatments increase SEMA7A expression, likely through the action of other hormone receptors such as the androgen receptor, which also increases with long term estrogen deprivation. Further, in ER+ cell lines, overexpression of SEMA7A promotes in vitro growth in the face of estrogen-deprivation, tamoxifen, or fulvestrant treatments. In vivo, SEMA7A promotes fulvestrant resistance in the primary tumor and induces lung metastases. Finally, we report that pro-survival signaling is a therapeutic vulnerability of ER+SEMA7A+ tumors. Conclusion: These studies describe that SEMA7A promotes drug resistance in ER+ BC. We propose that targeting pro-survival signaling may prove efficacious for treating SEMA7A+ tumors, which are less likely to respond to endocrine therapies.

Hormonal Regulation of Semaphorin 7a Promotes Therapeutic Resistance in ER+ Breast Cancer

The Grainyhead-like protein family, composed of GRHL1, GRHL2, and GRHL3, are nuclear transcription factors that regulate epithelial differentiation. GRHL2 has been associated with several nuclear hormone receptors, including progesterone receptor (PR), androgen receptor (AR), and more recently, estrogen receptor (ER). In breast cancer, GRHL2 has been shown to both activate ER-dependent enhancers through FOXA1 and MLL3-mediated deposition of the activating histone mark H3K4me1 and repress enhancers via inhibition of the histone acetyltransferase p300. Cistromic analysis by our group of ER phosphorylated at serine 118 (pS118-ER), a form of transcriptionally active ER, found an enrichment of the GRHL motif near pS118-ER binding sites. Despite these findings, the direct relationship between GRHL2 and ER transcriptional function and how that relationship influences ER-positive breast cancer growth and differentiation is not well-defined. To explore the relationship between GRHL2 and pS118-ER further, we used transcriptomic and cistromic analysis of ER-positive cells lacking GRHL2 to determine the impact of the loss of GRHL2 on cellular and transcriptional responses to estrogen. This analysis identified a subset of genes that are controlled by both GRHL2 and estrogen. In addition, CRISPR engineered T47D cells lacking a portion of the GRHL2 transactivation domain (ΔTAD) demonstrate reduced nuclear ER levels and reduced ER chromatin occupancy. Gene expression analysis of ΔTAD-GRHL2 cells showed increased GRHL3expression, and ChIP analysis revealed increased Pol II occupancy at the GRHL3promoter, suggesting that there may be a compensatory mechanism within the GRHL family to regulate the transcriptome. Finally, ΔTAD-GRHL2 mutants reduced growth and colony formation relative to wild-type controls. Together, this work will provide an understanding of how transcriptionally active ER and GRHL2 selectively cooperate to regulate transcription, growth, and differentiation in ER-positive breast cancer.

The Role of GRHL2 in Facilitating pS118-ER Transcriptional Activity in Hormone-Dependent Breast Cancer

Background: Liver X Receptors (LXRα, β) are oxysterol sensing nuclear receptors that regulate lipogenesis, cholesterol homeostasis and immune cell function. While oxysterols are agonist ligands of LXRs, sulfated oxysterols, catalytically produced by the SULT2B1b sulfotransferase, are LXR-inert. Increased SULT2B1b expression leads to attenuation of LXR signaling. In a previous report, we showed that SULT2B1b is undetectable in clinical samples of castration-resistant prostate cancer (CRPC), and its level is significantly reduced in a subset of primary prostate cancer. In cell models, genetic ablation of SULT2B1b exacerbated aggressive traits of CRPC, evident from EMT-like activation, enhanced invasion, faster xenograft tumor growth and reduced cell adhesiveness and stiffness in single-cell atomic force microscopy analysis. AKR1C3, which promotes androgen biosynthesis and shows elevated expression in advanced prostate cancer, is markedly upregulated in SULT2B-depleted cells. Elevated AKR1C3 leads to activation of the ERK1/2 Map kinase survival signal in CRPC cells. Results: We report here that AKR1C3 upregulation is a consequence of enhanced LXRα signaling in SULT2B1b-deficient cells, since the upregulation was abolished in multiple cell models when LXRα was silenced by siRNAs or inactivated by the small molecule inhibitor SR9243, which is an LXRs-selective inverse agonist. Conversely, LXR agonism induced by an oxysterol, or by the synthetic ligand GW3965, resulted in elevated AKR1C3 expression. Consistent with a recent report that the nuclear receptor ERRα is a positive regulator of AKR1C3, we found that ERRα ablation prevented AKR1C3 upregulation in SULT2B1b-deficient cells. Notably, LXRα inactivation caused marked reduction of ERRα, indicating that ERRα functions downstream of LXRα to induce AKR1C3 and ERK1/2. Dependence of ERRα and AKR1C3 expression on LXRα was observed in both androgen receptor (AR)-positive and AR-negative CRPC cells. Elevated ERRα in prostate cancer is known to be associated with a poor disease outcome. This association may be in part due to ERRα activation by cholesterol, which is the endogenous agonist ligand for ERRα (Cell Metab 23: 479, 2016), and high cholesterol is a risk factor for aggressive prostate cancer. Furthermore, statins, which inhibit cholesterol biosynthesis, are beneficial to CRPC patients with elevated blood cholesterol. We identified two cholesterol-responsive ERRα-binding sites in the far upstream region of the AKR1C3 promoter. This result confirms that ERRα plays a direct role in the transcriptional upregulation of AKR1C3. Significance: Our study establishes a novel LXRα→ERRα→AKR1C3→ERK1/2 survival axis that is activated in CRPC cells under SULT2B1b deficiency. The LXRα→ERRα regulatory axis may be exploited for developing novel therapeutics against AR-positive and AR-negative CRPC.

Prostate Cancer Stimulation by a Novel Liver X Receptor (LXRα) → Estrogen Related Receptor (ERRα) Axis

Gut-derived hormones have been successfully developed as the therapeutic targets to combat the increasing prevalence of diabetes and obesity. G protein-coupled receptors (GPCRs) in the gastrointestinal (GI) tract are involved in maintaining glucose and energy homeostasis by regulating the release of gut hormones in response to luminal dietary nutrients as well as microbial metabolites. We identified that an orphan GPCR, Gpr17, was expressed in the intestinal epithelium and found that loss of intestinal Gpr17 expression increased gut incretin hormone secretion from enteroendocrine cells (EECs). However, it is unknown how Gpr17 ablation in the intestinal epithelium affects feeding behavior and satiety regulation. To address this question, we used genetic knockout approach to generate intestinal Gpr17-deficient mice and analyzed their feeding behavior. Here we show that intestinal Gpr17-deficient mice had similar growth curve, body composition, and ad libitum food intake compared with littermate controls. Interestingly, intestinal Gpr17-deficient mice responded to fasting-refeeding challenge with reduced fasting locomotor activity and less food intake after refeeding, suggesting increased satiety during the phase of rebound hyperphagia. Moreover, we performed fasting-refeeding challenge with Gpr17-deficient mice fed on high-fat diet (HFD), and our meal pattern analysis revealed that these mice had reduced meal duration of the first meal after refeeding. In conclusion, our genetic knockout studies in rodents showed that ablating intestinal Gpr17 increased satiety during rebound hyperphagia in the fasting-refeeding experimental paradigm. Intestinal Gpr17 could be developed as a therapeutic target to treat obesity by improving energy balance through gut hormone secretion and meal pattern control.?? 

Mice Deficient for an Intestinal G Protein-Coupled Receptor Expression Have Increased Satiety During Rebound Hyperphagia

INTRODUCTION: Gestational diabetes mellitus (GDM) is an increasingly frequent complication of pregnancy and its presence is related to the development of adverse maternal and fetal outcomes. Pregnancy is deeply influenced by the circadian rhythm and the misalignment of the maternal rhythm can lead to disturbances in the temporal organization of physiological and metabolic functions. Previously, the association between circadian rhythm disorders and diabetes has been well described in pregnancy. OBJECTIVE: To investigate the influence of chronotype on the development of maternal and fetal complications during pregnancy in GDM. METHODOLOGY: Prospective cohort study of patients with GDM. Clinical data and behavior questionnaires were collected by face- to- face interview. Questionnaires evaluated the chronotype (Morning-Eveningness-Questionnaire- MEQ), sleep quality (Pittsburgh Sleep Quality Index- PSQI), daytime sleepiness (Epworth Sleepiness Scale -ESS), depressive symptoms (Edinburgh Postnatal Depression Scale-EDPS) and insomnia (Insomnia Severity Index- ISI). Sleep diaries (14 days) and actigraphic record (5 to 7 days) were obtained. RESULTS: Overall, 305 2nd to 3rd trimester GDM patients were evaluated. Eighty-nine GDM patients completed the sleep diary and 53 performed a valid actigraphic registry. Amongst these, 49.5% were identified as morning chronotypes (MEQ≥59), 43.6% intermediate types (MEQ from 42 to 58) and 6.9% had evening type preference (MEQ<41). Evening preference patients were younger (p< 0.005), had more unstable marital status (P = 0.04), had worse sleep quality (p = 0.02); latter sleep midpoint (p= 0.01), higher prevalence of insomnia (p< 0.005) and depression (p= 0.004) before and during pregnancy. No differences were found in total sleep duration as recorded by sleep diary (p=0.4) or actigraphic measurements (p=0.83). Evening type preference in GDM was associated with pre-eclampsia (p= 0.02) and neonatal ICU admission (p= 0.03). CONCLUSION: This study suggests that the presence of the evening-type chronotype in pregnant women with GDM is associated with adverse pregnancy outcomes such as the development of hypertensive syndromes, insomnia and depressive symptoms. In addition, a higher prevalence of newborns admitted to the neonatal ICU was found in the offspring of GDM patients with evening preference.?? 

RAI Treatment of Adults with Hyperthyroidism is Safe with Regards to Cancer Risk

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