Arid1a inactivation in an Apc‐ and Pten‐defective mouse ovarian cancer model enhances epithelial differentiation and prolongs survival

Abstract

Inactivation of the ARID1A tumor suppressor gene is frequent in ovarian endometrioid (OEC) and clear cell carcinomas (OCCC), often in conjunction with mutations activating the PI3K/AKT and/or canonical Wnt signaling pathways. Prior work has shown that conditional bi-allelic inactivation of the Apc and Pten tumor suppressor genes in the mouse ovarian surface epithelium (OSE) promotes outgrowth of tumors that reflect the biological behavior and gene expression profiles of human OECs harboring comparable Wnt and PI3K/AKT pathway defects, though the mouse tumors are more poorly differentiated than their human tumor counterparts. We found that conditional inactivation of one or both Arid1a alleles in OSE concurrently with Apc and Pten inactivation unexpectedly prolonged survival of tumor-bearing mice and promoted striking epithelial differentiation of the cancer cells, resulting in morphological features akin to those in human OECs. Enhanced epithelial differentiation was linked to reduced expression of mesenchymal markers N-cadherin and vimentin, and increased expression of epithelial markers Crb3 and E-cadherin. Global gene expression profiling showed enrichment for genes associated with mesenchymal-to-epithelial transition in the Arid1a-deficient tumors. We also found that an activating (E545K) Pik3ca mutation, unlike Pten inactivation or Pik3ca H1047R mutation, cannot cooperate with Arid1a loss to promote ovarian cancer development in the mouse. Our results indicate the Arid1a tumor suppressor gene has a key role in regulating OEC differentiation, and paradoxically the mouse cancers with more initiating tumor suppressor gene defects had a less aggressive phenotype than cancers arising from fewer gene alterations.

Suppression of the SWI/SNF Component Arid1a Promotes Mammalian Regeneration

“…Since ARID1A loss-of-function mutations are commonly found in human cancer (Chan-On et al, 2013; Fujimoto et al, 2012; Guichard et al, 2012; Huang et al, 2012; Jiao et al, 2013), we tested if Arid1a is always a bona fide tumor suppressor. Neither global nor liver-specific Arid1a deficient mice spontaneously developed tumors by one year of age (Figure S4D,E), consistent with some reports showing that Arid1a loss alone is not tumorigenic (Chandler et al, 2015; Guan et al, 2014), and in some cases, are even protective against cancer (Helming et al, 2014; Zhai et al, 2015). Much additional investigation will be needed to evaluate impact of Arid1a loss in tumorigenesis.…”

The Tumor Suppressor ARID1A Controls Global Transcription via Pausing of RNA Polymerase II

“…First, the two paralogs seem to associate with different sets of transcription factors (Raab et al, 2015). Second, genetic mouse models suggest that the two proteins are functionally distinct (Celen et al, 2017; Goldman et al, 2016; Krosl et al, 2010; Vasileiou et al, 2015; Zhai et al, 2016). As a matter of fact, we found a subset of 1,817 genes that are not entirely rescued by ARID1B expression and remain dysregulated.…”

Microarray pathway analysis indicated that mitogen-activated protein kinase/extracellular signal-regulated kinase and insulin growth factor 1 signaling pathways were inhibited by small interfering RNA against AT‑rich interactive domain 1A in endometrial cancer

“…However, previous studies have primarily provided insight into the function of wild-type ARID1A (9,10). Furthermore, in EC, the majority of previous studies have focused on the loss of ARID1A expression as determined by immunohistochemistry or gene sequencing of mutations (7)(8)(9)(10)(11).…”

“…Furthermore, in EC, the majority of previous studies have focused on the loss of ARID1A expression as determined by immunohistochemistry or gene sequencing of mutations (7)(8)(9)(10)(11). Therefore, it remains unclear which signaling pathways are influenced by ARID1A mutations and which pathway molecules are targeted by ARID1A mutations in EC pathophysiology.…”