title: Tumor repressor protein 53 and steroid hormones provide a new paradigm for ovarian cancer metastases.
abstract: The functional status of the tumor repressor protein (TP53 or TRP53) is a defining feature of ovarian cancer. Mutant or null alleles of TP53 are expressed in greater than 90% of all high-grade serous adenocarcinomas. Wild-type TP53 is elevated in low-grade serous adenocarcinomas in women and in our Pten;Kras;Amhr2-Cre mutant mouse model. Disruption of the Trp53 gene in this mouse model did not lead to high-grade ovarian cancer but did increase expression of estrogen receptor α (ESR1) and markedly enhanced the responsiveness of these cells to estrogen. Specifically, when Trp53-positive and Trp53 null mutant mice were treated with estradiol or vehicle, only the Trp53 null and Esr1-positive tumors respond vigorously to estradiol in vivo and exhibit features characteristic of high-grade type ovarian cancer: invasive growth into the ovarian stroma, rampant metastases to the peritoneal cavity, and nuclear atypia. Estrogen promoted and progesterone suppressed the growth of Trp53 null ovarian tumors and tumor cells injected ip, sc, or when grown in matrigel. Exposure of the Trp53 depleted cells to estrogen also has a profound impact on the tumor microenvironment and immune-related events. These results led to the new paradigm that TRP53 status is related to the susceptibility of transformed ovarian surface epithelial cells to estradiol-induced metastases and nuclear atypia via increased levels of estradiol receptor α.
authors.affiliation: Department of Molecular and Cellular Biology (L.K.M., Z.L., V.D., Y.A.R., J.S.R.), and Department of Pathology (A.H.), Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030; and Department of Gynecologic Oncology (K.-K.W.), The University of Texas MD Anderson Cancer Center, Houston, Texas 77030.
authors.forename: Lisa K
authors.initials: LK
authors.lastname: Mullany
authors.forename: Zhilin
authors.initials: Z
authors.lastname: Liu
authors.forename: Kwong-Kwok
authors.initials: KK
authors.lastname: Wong
authors.forename: Victoria
authors.initials: V
authors.lastname: Deneke
authors.forename: Yi Athena
authors.initials: YA
authors.lastname: Ren
authors.forename: Alan
authors.initials: A
authors.lastname: Herron
authors.forename: JoAnne S
authors.initials: JS
authors.lastname: Richards
mesh_terms: D000230:Adenocarcinoma / Q000276:immunology / Q000378:metabolism* / Q000556:secondary; D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004958:Estradiol / Q000502:physiology*; D047628:Estrogen Receptor alpha / Q000378:metabolism; D005260:Female; D006801:Humans; D051379:Mice; D016688:Mice, Inbred NOD; D008822:Mice, Transgenic; D009368:Neoplasm Transplantation; D010051:Ovarian Neoplasms / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D010053:Ovary / Q000473:pathology; D011374:Progesterone / Q000502:physiology; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*
chemical_list: D047628:Estrogen Receptor alpha; D016159:Tumor Suppressor Protein p53; D011374:Progesterone; D004958:Estradiol