Ovarian Adenocarcinomas in the Laying Hen and Women Share Similar Alterations in p53, ras, and HER-2/neu

Division of Gynecologic Oncology, Evanston Northwestern Healthcare, Northwestern University, Evanston, Illinois, [corrected] USA.
Cancer Prevention Research (Impact Factor: 4.44). 02/2009; 2(2):114-21. DOI: 10.1158/1940-6207.CAPR-08-0065
Source: PubMed


We examined alterations in the p53 tumor suppressor gene and the ras and HER-2/neu oncogenes in chicken ovarian cancers to determine if these tumors have genetic alterations similar to those in human ovarian adenocarcinomas. Mutations in the p53 tumor suppressor gene and the H-ras and K-ras oncogenes were assessed by direct sequencing in 172 ovarian cancers obtained from 4-year-old birds enrolled at age 2 in two separate 2-year chemoprevention trials. Birds in trial B had approximately twice as many lifetime ovulations as those in trial A. Immunohistochemical staining for the HER-2/neu oncogene was done on a subset of avian ovarian and oviductal adenocarcinomas. Alterations in p53 were detected in 48% of chicken ovarian cancers. Incidence of p53 alterations varied according to the number of lifetime ovulations, ranging from 14% in trial A to 96% in trial B (P < 0.01). No mutations were seen in H-ras, and only 2 of 172 (1.2%) tumors had K-ras mutations. Significant HER-2/neu staining was noted in 10 of 19 ovarian adenocarcinomas but in only 1 of 17 oviductal adenocarcinomas. Similar to human ovarian cancers, p53 alterations are common in chicken ovarian adenocarcinomas and correlate with the number of lifetime ovulations. Ras mutations are rare, similar to high-grade human ovarian cancers. HER-2/neu overexpression is common and may represent a marker to exclude an oviductal origin in cancers involving both the ovary and oviduct.

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    • "The four histotypes observed in human are represented in the hen, although the endometrioid type is the predominant form found in the hen whereas the serous type is most prevalent in women [8]. Mutations in p53 are common in epithelial ovarian cancer (EOC) from both species [9]. Numerous characteristic markers are also shared between the tumors of the two species such as CA-125 [10], CYP1B1 [11], E-cadherin [12] and COX-1 [13]. "
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    ABSTRACT: Background The laying hen model of spontaneous epithelial ovarian cancer (EOC) is unique in that it is the only model that enables observations of early events in disease progression and is therefore also uniquely suited for chemoprevention trials. Previous studies on the effect of dietary flaxseed in laying hens have revealed the potential for both amelioration and prevention of ovarian cancer. The objective of this study was to assess the effect of flaxseed on genes and pathways that are dysregulated in tumors. We have used a bioinformatics approach to identify these genes, followed by qPCR validation, immunohistochemical localization, and in situ hybridization to visualize expression in normal ovaries and tumors from animals fed a control diet or a diet containing 10% flaxseed. Results Bioinformatic analysis of ovarian tumors in hens led to the identification of a group of highly up-regulated genes that are involved in the embryonic process of branching morphogenesis. Expression of these genes coincides with expression of E-cadherin in the tumor epithelium. Levels of expression of these genes in tumors from flax-fed animals are reduced 40-60%. E-cadherin and miR200 are both up-regulated in tumors from control-fed hens, whereas their expression is decreased 60-75% in tumors from flax-fed hens. This does not appear to be due to an increase in ZEB1 as mRNA levels are increased five-fold in tumors, with no significant difference between control-fed and flax-fed hens. Conclusions We suggest that nutritional intervention with flaxseed targets the pathways regulating branching morphogenesis and thereby alters the progression of ovarian cancer. Electronic supplementary material The online version of this article (doi:10.1186/1471-2164-15-709) contains supplementary material, which is available to authorized users.
    Full-text · Article · Aug 2014 · BMC Genomics
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    • "In this respect, steroid sex hormones were thought to be effective on leiomyomas of VL in poultry animals. Leiomyomas of oviduct and it's VL in hens share several histologic and biological features with human uterine leiomyomas8910. Our histochemical and immunohistochemical findings confirm that tumours found on the oviduct and it's VL of hens are derived from smooth muscle cells and there are association between tumorigenesis and ovarian sex steroid hormones. In conclusion, leiomyomas of the oviduct and its VL in hens were investigated both by histological and immunohistochemical means. "
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    ABSTRACT: Leiomyoma’s of the oviduct and its ventral ligament (VL) are common tumours of the domestic fowl which develop after the end of the first laying season. In the present study, macroscopic, microscopic, and immunohistochemical features of the leiomyomas of the reproductive tract and their prevalence were investigated in commercial laying hens. In 60-90 weeks old commercial laying hens, toward the end of the first laying period, the incidence of genital tract leiomyomas were determined as 10.43%. Of these, 95.81% were developed from oviduct VL and 4.19% were oviduct leiomyomas. These tumours were firm, round to oval and microscopically well-circumscribed, consisting of monomorphic spindle cells. In immunohistochemical examination with α-smooth muscle actin, desmin and vimentin, all tumours were found positive with these markers. To investigate the aetiological importance for tumourogenesis, the plasma concentrations of 17 β-oestradiol and progesterone levels were determined. Concentrations of 17 β-oestradiol and progesterone were higher in hens with tumours than that of non-tumour control animals. The results suggested that there was an association between the levels of 17 β-oestradiol and progesterone and the leiomyomas of genital tract in hens.
    Preview · Article · May 2014 · Kafkas Üniversitesi Veteriner Fakültesi Dergisi
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    • "Thus non-invasive methods for selecting hens for studies and for monitoring tumor progression are available. Furthermore, naturally occurring genetic mutations such as p53, RAS and Her2/neu are found in hen tumors [22], [23], [24]. Likewise, there is a growing list of proteins expressed in chicken ovarian tumors such as CA125 [25], mesothelin [26], COX 1 [27], [28], Selenium Binding Protein 1 [29], E-cadherin [30] and VEGF that are similarly altered in human ovarian tumors [17], [20], [31]. "
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    ABSTRACT: Spontaneous ovarian cancer in chickens resembles human tumors both histologically and biochemically. The goal was to determine if there are differences in lymphocyte content between normal ovaries and ovarian tumors in chickens as a basis for further studies to understand the role of immunity in human ovarian cancer progression. Hens were selected using grey scale and color Doppler ultrasound to determine if they had normal or tumor morphology. Cells were isolated from ovaries (n = 6 hens) and lymphocyte numbers were determined by flow cytometry using antibodies to avian CD4 and CD8 T and B (Bu1a) cells. Ovarian sections from another set of hens (n = 26) were assessed to verify tumor type and stage and to count CD4, CD8 and Bu1a immunostained cells by morphometric analysis. T and B cells were more numerous in ovarian tumors than in normal ovaries by flow cytometry and immunohistochemistry. There were less CD4+ cells than CD8+ and Bu1a+ cells in normal ovaries or ovarian tumors. CD8+ cells were the dominant T cell sub-type in both ovarian stroma and in ovarian follicles compared to CD4+ cells. Bu1a+ cells were consistently found in the stroma of normal ovaries and ovarian tumors but were not associated with follicles. The number of immune cells was highest in late stage serous tumors compared to endometrioid and mucinous tumors. The results suggest that similar to human ovarian cancer there are comparatively more immune cells in chicken ovarian tumors than in normal ovaries, and the highest immune cell content occurs in serous tumors. Thus, this study establishes a foundation for further study of tumor immune responses in a spontaneous model of ovarian cancer which will facilitate studies of the role of immunity in early ovarian cancer progression and use of the hen in pre-clinical vaccine trials.
    Full-text · Article · Sep 2013 · PLoS ONE
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