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Endometrial cancer is the most common gynecologic cancer and one of the only cancers for which incidence and mortality is steadily increasing. Although curable with surgery in the early stages, endometrial cancer presents a significant clinical challenge in the metastatic and recurrent setting with few novel treatment strategies emerging in the past fifty years. Ipatasertib (IPAT) is an orally bioavailable pan-AKT inhibitor, which targets all three AKT isoforms and has demonstrated anti-tumor activity in pre-clinical models, with clinical trials emerging for many cancer types. In the present study, the MTT assay was employed to evaluate the therapeutic efficacy of IPAT or IPAT in combination with paclitaxel (PTX) in endometrial cancer cell lines and primary cultures of endometrial cancer. The effect of IPAT and PTX on the growth of endometrial tumors was evaluated in a transgenic mouse model of endometrial cancer. Apoptosis was assessed using cleaved caspase assays and cellular stress was assessed using ROS, JC1 and tetramethylrhodamine ethyl ester assays. The protein expression levels of markers of apoptosis and cellular stress, and DNA damage were evaluated using western blotting and immunohistochemistry. IPAT significantly inhibited cell proliferation, caused cell cycle G1 phase arrest, and induced cellular stress and mitochondrial apoptosis in a dose dependent manner in human endometrial cancer cell lines. Combined treatment with low doses of IPAT and PTX led to synergistic inhibition of cell proliferation and induction of cleaved caspase 3 activity in the human endometrial cancer cell lines and the primary cultures. Furthermore, IPAT effectively reduced tumor growth, accompanied by decreased protein expression levels of Ki67 and phosphorylation of S6 in the Lkb1fl/flp53fl/fl mouse model of endometrioid endometrial cancer. The combination of IPAT and PTX resulted in increased expression of phosphorylated-H2AX and KIF14, markers of DNA damage and microtubule dysfunction respectively, as compared with IPAT alone, PTX alone or placebo-treated mice. The results of the present study provide a biological rationale to evaluate IPAT and the combination of IPAT and PTX in future clinical trials for endometrial cancer.

Background Perceived discrimination can undermine healthcare system trust and contribute to medical mistrust, creating barriers to effective survivorship care. Endometrial cancer survivors, who experience intersecting social, reproductive, and aging‐related challenges, remain understudied, and population‐level evidence on the relationship between discrimination and medical mistrust in this group is limited. Methods We analyzed enrollment survey data from the population‐based Carolina Endometrial Cancer Study. Perceived discrimination was measured using the 9‐item Everyday Discrimination Scale, categorized into tertiles (low, moderate, high). Medical mistrust was assessed using the 7‐item Medical Mistrust Index (MMI), dichotomized as ≥ 1 item endorsed. Modified Poisson regression models estimated adjusted prevalence ratios (aPRs) and 95% confidence intervals (CIs), adjusting for age at diagnosis, region, education, and caregiving support. Analyses were conducted overall and stratified by race, education, and geography, with sensitivity analyses of frequency‐ and chronicity‐based discrimination measures. Results Among 907 survivors (35% Black, mean age 60.9 years), nearly half reported moderate or high perceived discrimination, and more than 80% endorsed ≥ 1 MMI item. Compared with low discrimination, moderate (aPR = 1.20, 95% CI: 1.12–1.30) and high discrimination (aPR = 1.26, 95% CI: 1.17–1.34) were associated with a higher prevalence of mistrust. Associations were consistent across racial, educational, and geographic subgroups. Sensitivity analyses confirmed that both the frequency and intensity of discrimination were positively associated with mistrust. Conclusion Perceived discrimination was common and strongly associated with mistrust among endometrial cancer survivors. Our findings highlight the need for culturally responsive survivorship care and equity‐focused interventions to strengthen trust and engagement.

We conducted a preoperative window study of metformin in endometrial cancer (EC) patients and evaluated its antiproliferative, molecular and metabolic effects. Twenty obese women with endometrioid EC were treated with metformin (850 mg) daily for up to 4 weeks prior to surgical staging. Expression of the proliferation marker Ki‐67, estrogen receptor (ER), progesterone receptor (PR), adenosine monophosphate‐activated protein kinase (AMPK), and downstream targets of the mammalian target of rapamycin (mTOR) pathway were measured by immunohistochemistry. Global, untargeted metabolomics analysis of serum pre‐ and postmetformin treatment, and matched tumor, was performed. Metformin reduced proliferation by 11.75% (P = 0.008) based on the comparison of pre‐ and posttreatment endometrial tumors. A total of 65% of patients responded to metformin as defined by a decrease in Ki‐67 staining in their endometrial tumors post‐treatment. Metformin decreased expression of phosphorylated (p)‐AMPK (P = 0.00001), p‐Akt (P = 0.0002), p‐S6 (51.2%, P = 0.0002), p‐4E‐BP‐1 (P = 0.001), and ER (P = 0.0002) but not PR expression. Metabolomic profiling of serum indicated that responders versus nonresponders to treatment were more sensitive to metformin's effects on induction of lipolysis, which correlated with increased fatty acid oxidation and glycogen metabolism in matched tumors. In conclusion, metformin reduced tumor proliferation in a pre‐operative window study in obese EC patients, with dramatic effects on inhibition of the mTOR pathway. Metformin induced a shift in lipid and glycogen metabolism that was more pronounced in the serum and tumors of responders versus nonresponders to treatment.This study provides support for therapeutic clinical trials of metformin in obese patients with EC. Metformin significantly reduced proliferation, as assessed by Ki‐67 staining, in a preoperative window study in obese endometrial cancer patients, with parallel effects on inhibition of the mTOR pathway. Differences were found in the metabolic effects of metformin in the serum and endometrial tumors of responders versus nonresponders to treatment, including increased lipolysis, fatty acid oxidation, and glycogen metabolism in responders. This study provides support for therapeutic clinical trials of metformin in this obesity‐driven disease.

Endometrial epithelia are known to harbor cancer driver mutations in the absence of any pathologies, including mutations in PIK3CA. Insulin plays an important role in regulating uterine metabolism during pregnancy, and hyperinsulinemia is associated with conditions impacting fertility. Hyperinsulinemia also promotes cancer, but the direct action of insulin on mutated endometrial epithelial cells is unknown. Here, we treated 12Z endometriotic epithelial cells carrying the PIK3CA H1047R oncogene with insulin and examined transcriptomes by RNA-seq. While cells naively responded to insulin, the magnitude of differential gene expression (DGE) was nine times greater in PIK3CA H1047R cells, representing a synergistic effect between insulin signaling and PIK3CA H1047R expression. Interferon signaling and the unfolded protein response (UPR) were enriched pathways among affected genes. Insulin treatment in wild-type cells activated normal endoplasmic reticulum stress (ERS) response programs, while PIK3CA H1047R cells activated programs necessary to avoid ERS-induced apoptosis. PIK3CA H1047R expression alone resulted in overexpression (OE) of Viperin (RSAD2), which is involved in viral response and upregulated in the endometrium during early pregnancy. The transcriptional changes induced by insulin in PIK3CA H1047R cells were rescued by knockdown of Viperin, while Viperin OE alone was insufficient to induce a DGE response to insulin, suggesting that Viperin is necessary but not sufficient for the synergistic effect of PIK3CA H1047R and insulin treatment. We identified interferon signaling, viral response, and protein targeting pathways that are induced by insulin but dependent on Viperin in PIK3CA H1047R mutant cells. These results suggest that response to insulin signaling is altered in mutated endometriotic epithelial cells.

Circulating tissue factor (TF)‐expressing extracellular vesicles (EVs) are associated with thrombosis in several diseases, such as coronavirus disease 2019 (COVID‐19). Activity assays have higher sensitivity and specificity compared to antigen assays for measuring TF+ EVs in plasma. The MACSPlex Exosome Kit is designed to detect 37 exosomal surface epitopes, including TF, on EVs in plasma using various fluorescently labeled beads. The different EV‐bead complexes are detected by flow cytometry. A recent study used the MACSPlex Exosome Kit to measure levels of TF+ EVs in serum from patients with COVID‐19. To evaluate the ability of the MACSPlex Exosome Kit to detect TF on EVs in plasma. We measured levels of TF+ EVs isolated from plasma with or without TF detected using our in‐house EVTF activity assay and the MACSPlex Exosome Kit. The MACSPlex Exosome Kit gave a very low TF antigen signal (TF bead signal) compared to platelet‐derived CD41b+ EVs, which was used as a control. Lipopolysaccharide (LPS) increased levels of EVTF activity but not TF bead signal in four donors. Inhibition of TF reduced levels of EVTF activity but did not affect the TF bead signal in EVs isolated from plasma from LPS‐treated blood. Finally, we found no correlation between levels of EVTF activity and TF bead signal in EVs isolated from plasma from ovarian cancer patients (r = .16, P = .62). Our data suggest that the MACSPlex Exosome Kit gives a nonspecific signal for TF and does not have the sensitivity to detect TF+ EVs in plasma.

Given that prolonged exposure to estrogen and increased telomerase activity are associated with endometrial carcinogenesis, our objective was to evaluate the interaction between the MAPK pathway and estrogen induction of telomerase activity in endometrial cancer cells. Estradiol (E2) induced telomerase activity and hTERT mRNA expression in the estrogen receptor (ER)-α positive, Ishikawa endometrial cancer cell line. UO126, a highly selective inhibitor of MEK1/MEK2, inhibited telomerase activity and hTERT mRNA expression induced by E2. Similar results were also found after transfection with ERK 1/2-specific siRNA. Treatment with E2 resulted in rapid phosphorylation of p44/42 MAPK and increased MAPK activity which was abolished by UO126. The hTERT promoter contains two estrogen response elements (EREs), and luciferase assays demonstrate that these EREs are activated by E2. Exposure to UO126 or ERK 1/2-specific siRNA in combination with E2 counteracted the stimulatory effect of E2 on luciferase activity from these EREs. These findings suggest that E2-induction of telomerase activity is mediated via the MAPK pathway in human endometrial cancer cells.

Uterine carcinosarcoma is an aggressive variant of endometrial carcinoma characterized by unusual histologic features including discrete malignant epithelial and mesenchymal components (carcinoma and sarcoma). Recent studies have confirmed a monoclonal origin, and comprehensive genomic characterizations have identified mutations such as Tp53 and Pten. However, the biological origins and specific combination of driver events underpinning uterine carcinosarcoma have remained mysterious. Here, we explored the role of the tumor suppressor Fbxw7 in endometrial cancer through defined genetic model systems. Inactivation of Fbxw7 and Pten resulted in the formation of precancerous lesions (endometrioid intraepithelial neoplasia) and well-differentiated endometrioid adenocarcinomas. Surprisingly, all adenocarcinomas eventually developed into definitive uterine carcinosarcomas with carcinomatous and sarcomatous elements including heterologous differentiation, yielding a faithful genetically engineered model of this cancer type. Genomic analysis showed that most tumors spontaneously acquired Trp53 mutations, pointing to a triad of pathways (p53, PI3K, and Fbxw7) as the critical combination underpinning uterine carcinosarcoma, and to Fbxw7 as a key driver of this enigmatic endometrial cancer type. Lineage tracing provided formal genetic proof that the uterine carcinosarcoma cell of origin is an endometrial epithelial cell that subsequently undergoes a prominent epithelial–mesenchymal transition underlying the attainment of a highly invasive phenotype specifically driven by Fbxw7.

Functional inactivation of tumor suppressor genes drives cancer initiation, progression, and treatment responses. Most tumor suppressor genes are inactivated through 1 of 2 well-characterized mechanisms: DNA-level mutations, such as point mutations or deletions, and promoter DNA hypermethylation. Here, we report a distinct third mechanism of tumor suppressor inactivation based on alterations to the histone rather than DNA code. We demonstrated that PAX2 is an endometrial tumor suppressor recurrently inactivated by a distinct epigenetic reprogramming event in more than 80% of human endometrial cancers. Integrative transcriptomic, epigenomic, 3D genomic, and machine learning analyses showed that PAX2 transcriptional downregulation is associated with replacement of open/active chromatin features (H3K27ac/H3K4me3) with inaccessible/repressive chromatin features (H3K27me3) in a framework dictated by 3D genome organization. The spread of the repressive H3K27me3 signal resembled a pearl necklace, with its length modulated by cohesin loops, thereby preventing transcriptional dysregulation of neighboring genes. This mechanism, involving the loss of a promoter-proximal superenhancer, was shown to underlie transcriptional silencing of PAX2 in human endometrial cancers. Mouse and human preclinical models established PAX2 as a potent endometrial tumor suppressor. Functionally, PAX2 loss promoted endometrial carcinogenesis by rewiring the transcriptional landscape via global enhancer reprogramming. The discovery that most endometrial cancers originate from a recurring epigenetic alteration carries profound implications for their diagnosis and treatment.

Background Exposure to per- and poly-fluoroalkyl substances (PFAS) has been associated with significant alterations in female reproductive health. These include changes in menstrual cyclicity, timing of menarche and menopause, and fertility outcomes, as well as increased risk of endometriosis, all of which may contribute to an increased risk of endometrial cancer. The effect of PFAS on endometrial cancer cells, specifically altered treatment response and biology, however, remains poorly studied. Like other gynecologic malignancies, a key contributor to lethality in endometrial cancer is resistance to chemotherapeutics, specifically to platinum-based agents that are used as the standard of care for patients with advanced-stage and/or recurrent disease. Objectives To explore the effect of environmental exposures, specifically PFAS, on platinum-based chemotherapy response and mitochondrial function in endometrial cancer. Methods HEC-1 and Ishikawa endometrial cancer cells were exposed to sub-cytotoxic nanomolar and micromolar concentrations of PFAS/PFAS mixtures and were treated with platinum-based chemotherapy. Survival fraction was measured 48-h post-chemotherapy treatment. Mitochondrial membrane potential was evaluated in both cell lines following exposure to PFAS ± chemotherapy treatment. Results HEC-1 and Ishikawa cells displayed differing outcomes after PFAS exposure and chemotherapy treatment. Cells exposed to PFAS appeared to be less sensitive to carboplatin, with instances of increased survival fraction, indicative of platinum resistance, observed in HEC-1 cells. In Ishikawa cells treated with cisplatin, PFAS mixture exposure significantly decreased survival fraction. In both cell lines, increases in mitochondrial membrane potential were observed post-PFAS exposure ± chemotherapy treatment. Discussion Exposure of endometrial cancer cell lines to PFAS/PFAS mixtures had varying effects on response to platinum-based chemotherapies. Increased survival fraction post-PFAS + carboplatin treatment suggests platinum resistance, while decreased survival fraction post-PFAS mixture + cisplatin exposure suggests enhanced therapeutic efficacy. Regardless of chemotherapy sensitivity status, mitochondrial membrane potential findings suggest that PFAS exposure may affect endometrial cancer cell mitochondrial functioning and should be explored further.

Endometrial cancer is the most common gynecologic cancer in the US. Endometrial cancer survivors may experience changes in microbiome due to cancer treatment and other factors. The human microbiome plays a crucial role in maintaining the proper functioning of the body. A more diverse microbiome often indicates a healthier gut environment, while lower vaginal microbiome diversity, specifically a Lactobacillus-dominant vagitype, is associated with more favorable health outcomes. The objectives of this pilot study were to evaluate potential variation in stool and vaginal microbiome communities and to assess the feasibility and acceptability of self-sampling among endometrial cancer survivors. Endometrial cancer survivors (N = 50) enrolled in the Carolina Endometrial Cancer Study, a cohort of women diagnosed with endometrial cancer, were mailed Genotek vaginal swab and stool self-collection kits. Self-reported questionnaires assessed information on survivors' demographics, sexual and bowel function, and perspectives on the self-sampling processes. Tumor characteristics and cancer treatment information were assessed from medical records. Microbiota profiles were characterized by bacteria 16S rRNA amplicon sequencing. Overall, 48 vaginal swabs and 47 stool samples were obtained. Alpha (Shannon p = 0.04) and beta (Bray-Curtis p = 0.004) diversity of vaginal microbiome samples varied by cancer treatment, with higher microbial diversity after chemotherapy or radiation compared to surgery alone. In the surgery only group, 63% of samples were Lactobacillus-dominant compared to 17% among the chemotherapy or radiation group. Stool microbiome diversity did not vary by cancer treatment status. No statistically significant differences in alpha or beta diversity were observed in either vaginal or stool microbiome communities across racial subgroups or by sexual or bowel function. Self-collection of stool and vaginal microbiome samples is feasible and acceptable in cancer survivors. Our results suggest that radiation and chemotherapy for endometrial cancer may decrease the abundance of beneficial Lactobacillus and increase less favorable vaginal microbial diversity among endometrial cancer survivors.