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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 alpha (ERalpha; 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 signs of genomic instability. Estrogen promoted and progesterone suppressed the growth of Trp53 null ovarian tumors and tumor cells injected intraperitoneally (IP), subcutaneously (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 (OSE) cells to estradiol-induced metastases and genomic instability. This novel finding is relevant not only for women during their reproductive years but also for women on hormone (estradiol) replacement therapies. A direct comparison of ovarian surface epithelia cells from two different genotype mice

ORGANISM(S): Mus musculus

SUBMITTER: Zhilin Liu

PROVIDER: E-GEOD-51095 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Tumor repressor protein 53 and steroid hormones provide a new paradigm for ovarian cancer metastases.

Mullany Lisa K LK Liu Zhilin Z Wong Kwong-Kwok KK Deneke Victoria V Ren Yi Athena YA Herron Alan A Richards JoAnne S JS

Molecular endocrinology (Baltimore, Md.) 20130101 1

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 markedl ...[more]

PMID: 24264574

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Project description:The small G-protein KRAS is crucial for mediating gonadotropin-induced events associated with ovulation. However, constitutive expression of KrasG12D in granulosa cells disrupted normal follicle development leading to the persistence of abnormal follicle-like structures containing non-mitotic cells. To determine what factors mediate this potent effect of KrasG12D, gene profiling analyses were done. We also analyzed KrasG12D;Cyp19-Cre and KrasG12D;Pgr-Cre mutant mouse models that express Cre prior to or after the initiation of granulosa cell differentiation, respectively. KrasG12D induced cell cycle arrest in granulosa cells of the KrasG12D;Cyp19-Cre mice but not in the KrasG12D;Pgr-Cre mice, documenting the cell context specific effect of KrasG12D. Expression of KrasG12D silenced the Kras gene, reduced cell cycle activator genes and impaired expression of granulosa cell and oocyte specific genes. Conversely, levels of PTEN and phosphorylated p38MAPK increased markedly in the mutant granulosa cells. Because disrupting Pten in granulosa cells leads to increased proliferation and survival, Pten was disrupted in the KrasG12D mutant mice. The Pten/Kras mutant mice were infertile but lacked GCTs. By contrast, the Ptenfl/fl;KrasG12D;Amhr2-Cre mice developed aggressive ovarian surface epithelial (OSE) cell tumors that did not occur in the Ptenfl/fl;KrasG12D;Cyp19-Cre or Ptenfl/fl;KrasG12D;Pgr-Cre mouse strains. These data document unequivocally that Amhr2-Cre is expressed in and mediates allelic recombination of oncogenic genes in OSE cells. That KrasG12D/Pten mutant granulosa cells do not transform but rather undergo cell cycle arrest indicates that they resist the oncogenic insults of Kras/Pten by robust self-protecting mechanisms that silence the Kras gene and elevate PTEN and phospho-p38MAPK. Experiment Overall Design: Whole ovaries were collected from 26-day-old wild type mice, 26-day-old K-ras conditional mutant mice and 3-month-old K-ras conditional mutant mice. The gene expression profiles of these samples were compared using microarray method.

Project description:Stable activation of the WNT signaling effector beta-catenin (CTNNB1(ex3) in ovarian granulosa cells results in the formation of premalignant lesions that develop into granulosa cell tumors (GCTs) spontaneously later in life. Loss of the tumor suppressor gene Pten accelerates GCT formation in the CTNNB1 strain. Conversely, expression of oncogenic KRASG12D causes the dramatic arrest of proliferation, differentiation and apoptosis in granulosa cells, and consequently, small abnormal follicle-like structures devoid of oocytes accumulate in the ovary. Because of the potent anti-proliferative effects of KRASG12D in granulosa cells, we sought to determine if KRASG12D would block precancerous lesion and tumor formation in follicles of the CTNNB1 mutant mice. Unexpectedly, transgenic Ctnnb1;Kras mutant mice developed early-onset GCTs leading to premature death in a manner similar to theCtnnb1;Pten mutant mice. Moreover, the GCTs in the Ctnnb1;Kras mutant mice exhibited increased GC proliferation, decreased apoptosis and impaired differentiation. Microarray and RT-PCR analyses revealed that ovaries from mice expressing dominant-stable CTNNB1 with either Pten loss or KRAS activation were unpredictably similar. Specifically, gene regulatory processes induced by CTNNB1 were mostly enhanced by either KRAS activation or Pten loss in remarkably similar patterns and degree. Furthermore, the concomitant activation of CTNNB1 and KRAS in Sertoli cells resulted in the development of granulosa cell tumors of the testis. RT-PCR studies showed a partial overlap in gene regulatory processes associated with tumor development in the ovary and testis. Together, these results suggest that KRAS activation and Pten loss induce GCT development from premalignant lesions via highly similar molecular mechanisms. four samples: average of two wild type samples (previously submitted as GSM403220 and GSM403221), beta-Catenin constitutively active mutant, beta-Catenin;Pten double mutant, and beta-Catenin;Kras(G12D) double mutant

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Tumor repressor protein 53 and steroid hormones provide a new paradigm for ovarian cancer metastases

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Tumor repressor protein 53 and steroid hormones provide a new paradigm for ovarian cancer metastases.

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