title: Mutant p53 Promotes Epithelial Ovarian Cancer by Regulating Tumor Differentiation, Metastasis, and Responsiveness to Steroid Hormones.
abstract: Mutations in the tumor protein p53 (TP53) are the most frequently occurring genetic events in high-grade ovarian cancers, especially the prevalence of the Trp53(R172H)-mutant allele. In this study, we investigated the impact of the Trp53(R172H)-mutant allele on epithelial ovarian cancer (EOC) in vivo We used the Pten/Kras(G12D)-mutant mouse strain that develops serous EOC with 100% penetrance to introduce the mutant Trp53(R172H) allele (homolog for human Trp53(R172H)). We demonstrate that the Trp53(R172H) mutation promoted EOC but had differential effects on disease features and progression depending on the presence or absence of the wild-type (WT) TP53 allele. Heterozygous WT/Trp53(R172H) alleles facilitated invasion into the ovarian stroma, accelerated intraperitoneal metastasis, and reduced TP53 transactivation activity but retained responsiveness to nutlin-3a, an activator of WT TP53. Moreover, high levels of estrogen receptor α in these tumors enhanced the growth of both primary and metastatic tumors in response to estradiol. Ovarian tumors homozygous for Trp53(R172H) mutation were undifferentiated and highly metastatic, exhibited minimal TP53 transactivation activity, and expressed genes with potential regulatory functions in EOC development. Notably, heterozygous WT/Trp53(R172H) mice also presented mucinous cystadenocarcinomas at 12 weeks of age, recapitulating human mucinous ovarian tumors, which also exhibit heterozygous TP53 mutations (∼50%-60%) and KRAS mutations. Therefore, we present the first mouse model of mucinous tumor formation from ovarian cells and supporting evidence that mutant TP53 is a key regulator of EOC progression, differentiation, and responsiveness to steroid hormones. Cancer Res; 76(8); 2206-18. ©2016 AACR.
authors.affiliation: Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas.
authors.forename: Yi A
authors.initials: YA
authors.lastname: Ren
authors.affiliation: Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas.
authors.forename: Lisa K
authors.initials: LK
authors.lastname: Mullany
authors.affiliation: Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas.
authors.forename: Zhilin
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Department of Pathology & Immunology, Baylor College of Medicine, Houston, Texas.
authors.forename: Alan J
authors.initials: AJ
authors.lastname: Herron
authors.affiliation: Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas. joanner@bcm.edu kkwong@mdanderson.org.
authors.forename: Kwong-Kwok
authors.initials: KK
authors.lastname: Wong
authors.affiliation: Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas. joanner@bcm.edu kkwong@mdanderson.org.
authors.forename: JoAnne S
authors.initials: JS
authors.lastname: Richards
mesh_terms: D000818:Animals; D000077216:Carcinoma, Ovarian Epithelial; D002454:Cell Differentiation / Q000235:genetics*; D018450:Disease Progression; D004958:Estradiol / Q000502:physiology*; D016158:Genes, p53; D006579:Heterozygote; D051379:Mice; D009362:Neoplasm Metastasis / Q000235:genetics*; D009375:Neoplasms, Glandular and Epithelial / Q000235:genetics / Q000473:pathology*; D010051:Ovarian Neoplasms / Q000235:genetics / Q000473:pathology*
chemical_list: D004958:Estradiol