Co-existing TP53 and ARID1A mutations promote aggressive endometrial tumorigenesis

Abstract

TP53 and ARID1A are frequently mutated across cancer but rarely in the same primary tumor. Endometrial cancer has the highest TP53-ARID1A mutual exclusivity rate. However, the functional relationship between TP53 and ARID1A mutations in the endometrium has not been elucidated. We used genetically engineered mice and in vivo genomic approaches to discern both unique and overlapping roles of TP53 and ARID1A in the endometrium. TP53 loss with oncogenic PIK3CAH1047R in the endometrial epithelium results in features of endometrial hyperplasia, adenocarcinoma, and intraepithelial carcinoma. Mutant endometrial epithelial cells were transcriptome profiled and compared to control cells and ARID1A/PIK3CA mutant endometrium. In the context of either TP53 or ARID1A loss, PIK3CA mutant endometrium exhibited inflammatory pathway activation, but other gene expression programs differed based on TP53 or ARID1A status, such as epithelial-to-mesenchymal transition. Gene expression patterns observed in the genetic mouse models are reflective of human tumors with each respective genetic alteration. Consistent with TP53-ARID1A mutual exclusivity, the p53 pathway is activated following ARID1A loss in the endometrial epithelium, where ARID1A normally directly represses p53 pathway genes in vivo, including the stress-inducible transcription factor, ATF3. However, co-existing TP53-ARID1A mutations led to invasive adenocarcinoma associated with mutant ARID1A-driven ATF3 induction, reduced apoptosis, TP63+ squamous differentiation and invasion. These data suggest TP53 and ARID1A mutations drive shared and distinct tumorigenic programs in the endometrium and promote invasive endometrial cancer when existing simultaneously. Hence, TP53 and ARID1A mutations may co-occur in a subset of aggressive or metastatic endometrial cancers, with ARID1A loss promoting squamous differentiation and the acquisition of invasive properties.

FOXA2 suppresses endometrial carcinogenesis and epithelial-mesenchymal transition by regulating enhancer activity

“…There were no obvious sarcomatous elements in any of the tumors. High-grade nuclear atypia (consistent with severe aneuploidy) was not observed, as in most prior mouse models ( 48 – 51 ). Thus, histologically, the Foxa2 / Pten tumors resembled well-differentiated (i.e., grade 1) human endometrioid adenocarcinomas ( Figure 4, F and G ).…”

“…We then explored the possibility that Tp53 mutations occur in the tumors by p53 IHC (a sensitive and specific surrogate of mutations) at necropsy in n = 23 mice from the survival analysis. None of the tumors exhibited p53 mutant (overexpressing) clones, which provides an argument that, unlike some other mouse models and human cancer types, p53 mutation is not essential for Foxa2 -driven tumors ( 43 , 44 , 48 , 51 , 52 ). Taken together, these results demonstrated that Foxa2 was a potent tumor suppressor where functional inactivation cooperated with Pten loss.…”

Deciphering the Active Compounds and Mechanisms of HSBDF for Treating ALI via Integrating Chemical Bioinformatics Analysis

“…The pharmacological study suggested that G. baccata extract can upregulate AKT1 gene expressions to protect the cells against oxidative damage and inflammation ( Martínez et al, 2021 ). Moreover, the studies also suggested that TP53, PIK3R1, and PIK3CA were vital for inflammation ( Eyileten et al, 2018 ; Busbee et al, 2021 ; Reske et al, 2021 ). Accordingly, the results indicate that emodin, aloe-emodin, rhein, luteolin, and quercetin may play an important role in inhibiting anti-inflammatory and anti-oxidative damage.…”

Endometrial Epithelial ARID1A Is Required for Uterine Immune Homeostasis during Early Pregnancy

“…A more plausible mechanism for the triggering of extraordinary inflammation in Ltf iCre/+ Arid1a f/f pregnant uteri is suggested by the fact that epithelial cells in the uterus as well as in other tissue types are known to produce TNF, CSF2, and other proinflammatory cytokines in certain circumstances [ 42 , 58 , 59 , 60 , 61 ]. In fact, ARID1A has been shown to directly bind near the promoter regions of Il36a , Tnfsf13 , and other TNF-signaling related genes in the murine endometrial epithelium [ 30 ]. Furthermore, in 12Z endometriotic epithelial cells, genes bound by ARID1A and upregulated by knockdown of ARID1A expression include TNF signaling-related and inflammatory response pathway genes [ 29 ].…”

“…Furthermore, studies using mouse models have shown that deletion of uterine Arid1a drives increased endometriosis-like lesion establishment and causes endometrial-factor infertility related to disrupted P4 and E2 signaling [ 22 , 24 , 28 ]. Focused study on the role of ARID1A in the endometrial epithelium has revealed its critical cell-type-specific roles of maintaining epithelial identity and enabling gland development and function in pregnancy [ 29 , 30 , 31 ]. Deletion of Arid1a in the adult mouse endometrial epithelium led to early pregnancy defects through attenuation of forkhead box A2 (FOXA2) expression and LIF secretion from uterine glands.…”