Arid1a inactivation in an Apc- and Pten-defective mouse ovarian cancer model enhances epithelial differentiation and prolongs survival.
Inactivation of the ARID1A tumour suppressor gene is frequent in ovarian endometrioid (OEC) and clear cell (OCCC) carcinomas, often in conjunction with mutations activating the PI3K-AKT and/or canonical Wnt signalling pathways. Prior work has shown that conditional bi-allelic inactivation of the Apc and Pten tumour suppressor genes in the mouse ovarian surface epithelium (OSE) promotes outgrowth of tumours that reflect the biological behaviour and gene expression profiles of human OECs harbouring comparable Wnt and PI3K-AKT pathway defects, although the mouse tumours are more poorly differentiated than their human tumour counterparts. We found that conditional inactivation of one or both Arid1a alleles in OSE concurrently with Apc and Pten inactivation unexpectedly prolonged the survival of tumour-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 the mesenchymal markers N-cadherin and vimentin, and increased expression of the epithelial markers Crb3 and E-cadherin. Global gene expression profiling showed enrichment for genes associated with mesenchymal-epithelial transition in the Arid1a-deficient tumours. 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 that the Arid1a tumour suppressor gene has a key role in regulating OEC differentiation, and paradoxically the mouse cancers with more initiating tumour suppressor gene defects had a less aggressive phenotype than cancers arising from fewer gene alterations. Microarray data have been deposited in NCBI's Gene Expression Omnibus (GSE67695).
Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, USA.
Yali
Y
Zhai
Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor, MI, USA.
Rork
R
Kuick
Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, USA.
Courtney
C
Tipton
Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, USA.
Rong
R
Wu
Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, USA.
Michael
M
Sessine
Department of Cardiac Surgery, University of Michigan Medical School, Ann Arbor, MI, USA.
Zhong
Z
Wang
Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN, USA.
Suzanne J
SJ
Baker
Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, USA.|Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, USA.|Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI, USA.
Eric R
ER
Fearon
Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, USA.|Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, USA.|Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI, USA.
Kathleen R
KR
Cho
D018262:Adenocarcinoma, Clear Cell / Q000235:genetics / Q000473:pathology; D000818:Animals; D015153:Blotting, Western; D018269:Carcinoma, Endometrioid / Q000235:genetics / Q000473:pathology; D002454:Cell Differentiation / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics*; D004195:Disease Models, Animal; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics; D004848:Epithelium / Q000473:pathology; D005260:Female; D017491:Genes, APC; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D009687:Nuclear Proteins / Q000235:genetics*; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000473:pathology*; D051059:PTEN Phosphohydrolase / Q000235:genetics*; D046888:Tissue Array Analysis; D014157:Transcription Factors; D059467:Transcriptome
C511511:Arid1a protein, mouse; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D014157:Transcription Factors; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse
mesenchymal-epithelial transition; mouse ovarian cancer model; ovarian endometrioid carcinoma