In vivo modeling of metastatic human high-grade serous ovarian cancer in mice

Metastasis is responsible for 90% of human cancer mortality, yet it remains a challenge to model human cancer metastasis in vivo. Here we describe mouse models of high-grade serous ovarian cancer, also known as high-grade serous carcinoma (HGSC), the most common and deadliest human ovarian cancer type. Mice genetically engineered to harbor Dicer1 and Pten inactivation and mutant p53 robustly replicate the peritoneal metastases of human HGSC with complete penetrance. Arising from the fallopian tube, tumors spread to the ovary and metastasize throughout the pelvic and peritoneal cavities, invariably inducing hemorrhagic ascites. Widespread and abundant peritoneal metastases ultimately cause mouse deaths (100%). Besides the phenotypic and histopathological similarities, mouse HGSCs also display marked chromosomal instability, impaired DNA repair, and chemosensitivity. Faithfully recapitulating the clinical metastases as well as molecular and genomic features of human HGSC, this murine model will be valuable for elucidating the mechanisms underlying the development and progression of metastatic ovarian cancer and also for evaluating potential therapies

Nitroreduction of 4-nitropyrene is primarily responsible for DNA adduct formation in the mammary gland of female CD rats

We determined whether DNA adducts derived from 4-nitropyrene (4-NP) are formed via nitroreduction or ring oxidation. DNA adduct markers derived from both pathways were prepared and, consequently, were compared with those obtained in vivo in rats treated with 4-NP. Following in vitro reaction of 9,10-epoxy-9,10-dihydro-4-nitropyrene (4-NP-9,10-epoxide), an intermediate metabolite derived from ring oxidation of 4-NP, with calf thymus DNA (average level of binding in two determinations was 8.5 nmol/mg of DNA), DNA was enzymatically hydrolyzed to deoxyribonucleosides and the DNA hydrolysates were analyzed by HPLC. Electrospray mass and 1H NMR spectra of the major products indicated that these adducts are deoxyguanosine (dG) derivatives that resulted from N2-dG substitution at the 9- or 10-position of the pyrene nucleus. However, these adducts were not detected in vivo in the rat mammary gland and liver following the administration of 4-NP. Nitroreduction of 4-NP catalyzed by xanthine oxidase in the presence of DNA resulted in three major putative DNA adducts (level of binding of 12.0 ± 1.1 nmol/mg of DNA, n = 4) designated as peak 1 (46%), peak 2 (25%), and peak 3 (17%). Although peak 1 was further resolved into peaks 1a and lb, both were unstable and gradually decomposed to peak 2, and the latter was unequivocally identified as pyrene- 4,5-dione. On the basis of electrospray mass spectral analysis, peak 3 was tentatively identified as a deoxyinosine-derived 4-aminopyrene adduct. None of the adducts derived from nitroreduction of 4-NP catalyzed by xanthine oxidase coeluted with the synthetic standard N-(deoxyguanosin-8-yl)-4- aminopyrene prepared by reacting dG with N-acetoxy-4-aminopyrene. Nevertheless, HPLC analysis of the hydrolysates of liver and mammary DNA obtained from rats treated with [3H]-4-NP yielded four radioactive peaks, all of which coeluted with the markers derived from the nitroreduction pathway. These results indicate that nitroreduction is primarily responsible for DNA adduct formation in the liver and, especially, in the mammary gland which is the organ susceptible to carcinogenesis by this environmental agent

Targeting progesterone signaling prevents metastatic ovarian cancer

Effective cancer prevention requires the discovery and intervention of a factor critical to cancer development. Here we show that ovarian progesterone is a crucial endogenous factor inducing the development of primary tumors progressing to metastatic ovarian cancer in a mouse model of high-grade serous carcinoma (HGSC), the most common and deadliest ovarian cancer type. Blocking progesterone signaling by the pharmacologic inhibitor mifepristone or by genetic deletion of the progesterone receptor (PR) effectively suppressed HGSC development and its peritoneal metastases. Strikingly, mifepristone treatment profoundly improved mouse survival (∼18 human years). Hence, targeting progesterone/PR signaling could offer an effective chemopreventive strategy, particularly in high-risk populations of women carrying a deleterious mutation in the BRCA gene