title: Global deletion of Trp53 reverts ovarian tumor phenotype of the germ cell-deficient white spotting variant (Wv) mice.
abstract: White spotting variant (Wv) mice are spontaneous mutants attributed to a point mutation in the c-Kit gene, which reduces the tyrosine kinase activity to around 1% and affects the development of melanocytes, mast cells, and germ cells. Homozygous mutant mice are sterile but can live nearly a normal life span. The female Wv mice have a greatly reduced ovarian germ cell and follicle reserve at birth, and the remaining follicles are largely depleted soon after the females reach reproductive stage at around 7 weeks of age. Consequently, ovarian epithelial tumors develop in 100% of Wv females by 3 to 4 months of age. These tumors, called tubular adenomas, are benign but can become invasive in older Wv mice. We tested if additional genetic mutation(s) could convert the benign ovarian epithelial tumors to malignant tumors by crossing the Wv mutant into the Trp53 knockout background. Surprisingly, we found that global deletion of Trp53 suppressed the development of ovarian tubular adenomas in Wv mice. The ovaries of Wv/Wv; Trp53 (-/-) mice were covered by a single layer of surface epithelium and lacked excessive epithelial proliferation. Rather, the ovaries contained a small number of follicles. The presence of ovarian follicles and granulosa cells, as indicated by Pgc7 and inhibin-alpha expression, correlated with the absence of epithelial lesions. A reduction of Pten gene dosage, as in Wv/Wv; Pten (+/-) mice, produced a similar, though less dramatic, phenotype. We conclude that deletion of Trp53 prolongs the survival of ovarian follicles in Wv mice and consequently prevents the proliferation of ovarian epithelial cells and development of ovarian tubular adenomas. The results suggest that various cell types within the ovary communicate and mutually modulate, and an intact tissue environment is required to ensure homeostasis of ovarian surface epithelial cells. Especially, the current finding emphasizes the importance of ovarian follicles in suppressing the hyperplastic growth of ovarian epithelial cells, dominating over the loss of p53.
authors.affiliation: Ovarian Cancer Program, Fox Chase Cancer Center, Philadelphia, PA 19111.
authors.forename: Kathy Qi
authors.initials: KQ
authors.lastname: Cai
authors.affiliation: Sylvester Comprehensive Cancer Center, Department of Cell Biology, University of Miami Miller School of Medicine, Miami, FL 33136; Department of Medicine, University of California at San Diego, La Jolla, CA 92093.
authors.forename: Ying
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Sylvester Comprehensive Cancer Center, Department of Cell Biology, University of Miami Miller School of Medicine, Miami, FL 33136.
authors.forename: Elizabeth R
authors.initials: ER
authors.lastname: Smith
authors.affiliation: Ovarian Cancer Program, Fox Chase Cancer Center, Philadelphia, PA 19111.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Smedberg
authors.affiliation: Ovarian Cancer Program, Fox Chase Cancer Center, Philadelphia, PA 19111.
authors.forename: Dong-Hua
authors.initials: DH
authors.lastname: Yang
authors.affiliation: Ovarian Cancer Program, Fox Chase Cancer Center, Philadelphia, PA 19111.
authors.forename: Wan-Lin
authors.initials: WL
authors.lastname: Yang
authors.affiliation: Sylvester Comprehensive Cancer Center, Department of Cell Biology, University of Miami Miller School of Medicine, Miami, FL 33136. Electronic address: xxu2@med.miami.edu.
authors.forename: Xiang-Xi
authors.initials: XX
authors.lastname: Xu
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000818:Animals; D002277:Carcinoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation; D004195:Disease Models, Animal; D005260:Female; D017353:Gene Deletion; D018628:Gene Dosage; D015870:Gene Expression; D007265:Inhibins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D009154:Mutation; D009569:Nitric Oxide / Q000096:biosynthesis; D006080:Ovarian Follicle / Q000378:metabolism / Q000473:pathology; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D051059:PTEN Phosphohydrolase / Q000235:genetics; D010641:Phenotype; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
chemical_list: D016159:Tumor Suppressor Protein p53; C094377:inhibin-alpha subunit; D009569:Nitric Oxide; D007265:Inhibins; D019009:Proto-Oncogene Proteins c-kit; D051059:PTEN Phosphohydrolase