BackgroundIncreasing evidence suggests that forkhead box A1 (FOXA1) is frequently dysregulated in many types of human cancers. However, the exact function and mechanism of FOXA1 in human endometrial cancer (EC) remains unclear.MethodsFOXA1 expression, androgen receptor (AR) expression, and the relationships of these two markers with clinicopathological factors were determined by immunohistochemistry analysis. FOXA1 and AR were up-regulated by transient transfection with plasmids, and were down-regulated by transfection with siRNA or short hairpin RNA (shRNA). The effects of FOXA1 depletion and FOXA1 overexpression on AR-mediated transcription as well as Notch pathway and their impact on EC cell proliferation were examined by qRT-PCR, western blotting, co-immunoprecipitation, ChIP-PCR, MTT, colony-formation, and xenograft tumor–formation assays.ResultsWe found that the expression of FOXA1 and AR in ECs was significantly higher than that in a typical hyperplasia and normal tissues. FOXA1 expression was significantly correlated with AR expression in clinical tissues. High FOXA1 levels positively correlated with pathological grade and depth of myometrial invasion in EC. High AR levels also positively correlated with pathological grade in EC. Moreover, the expression of XBP1, MYC, ZBTB16, and UHRF1, which are downstream targets of AR, was promoted by FOXA1 up-regulation or inhibited by FOXA1 down-regulation. Co-immunoprecipitation showed that FOXA1 interacted with AR in EC cells. ChIP-PCR assays showed that FOXA1 and AR could directly bind to the promoter and enhancer regions upstream of MYC. Mechanistic investigation revealed that over-expression of Notch1 and Hes1 proteins by FOXA1 could be reversed by AR depletion. In addition, we showed that down-regulation of AR attenuated FOXA1-up-regulated cell proliferation. However, AR didn’t influence the promotion effect of FOXA1 on cell migration and invasion. In vivo xenograft model, FOXA1 knockdown reduced the rate of tumor growth.ConclusionsThese results suggest that FOXA1 promotes cell proliferation by AR and activates Notch pathway. It indicated that FOXA1 and AR may serve as potential gene therapy in EC.

Objective: To investigate the effects of body mass index (BMI) on assisted reproductive outcomes with the freeze-all strategy for patients with polycystic ovary syndrome (PCOS). Design: Retrospective cohort study. Setting: Tertiary care academic medical center. Patient(s): A total of 3,079 women with PCOS across different BMIs at our institution from January 2015 to May 2017 were stratified into cohorts. Intervention(s): None. Main Outcome Measure(s): Implantation rate, clinical pregnancy rate, early miscarriage rate, and live birth rate. Result(s): The live birth rate was most favorable in underweight (BMI < 18.5 kg/m 2 ) and normal weight cohorts (18.5 % BMI < 25 kg/ m 2 ) and progressively decreased as BMI increased. Moreover, the obese cohort (BMI R 30 kg/m 2 ) of patients with PCOS who had frozen ET cycles had a relatively high early miscarriage rate. Conclusion(s):The live birth rates are highest in underweight and normal weight patients with PCOS undergoing IVF with the freeze-all strategy. Furthermore, there is a progressive and statistically significant decrease in the live birth rate and an increase in the miscarriage rate in obese patients with PCOS. (Fertil Steril Ò 2019;112:1172-9. Ó2019 by American Society for Reproductive Medicine.) El resumen está disponible en Español al final del artículo.