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  • About
  • The Global ETD Search service is a free service for researchers to find electronic theses and dissertations. This service is provided by the Networked Digital Library of Theses and Dissertations.
    Our metadata is collected from universities around the world. If you manage a university/consortium/country archive and want to be added, details can be found on the NDLTD website.
1

The influence of chronic, systemic inflammation in the progression of epithelial ovarian cancer

Kerr, Amanda 28 August 2012 (has links)
Epidemiological studies have described a link between chronic inflammatory conditions, such as diabetes or obesity, and EOC suggesting that systemic inflammation may increase the risk of the disease. The purpose of this study was to identify the impact of prolonged exposure to low-grade inflammation on EOC tumorigenicity. We hypothesized that exposure to this inflammation would accelerate ovarian tumor growth. In vitro, normal and transformed ovarian epithelial cells had limited responsiveness to inflammatory cytokines. In vivo, LPS-induced low-grade chronic systemic inflammation accelerated EOC progression primarily through enhanced angiogenesis. Evaluation of the relationships between chronic systemic inflammation and EOC may provide a role for anti-inflammatory treatment in combinational EOC therapies. Additionally, as the rate of metabolic disorders increases in the Western world the results from this work may facilitate the advancement of complimentary therapeutic interventions for other cancers that are influenced by inflammation.
2

Steroid signalling in the human ovarian surface epithelium wound healing

Papacleovoulou, Georgia January 2009 (has links)
The human ovarian surface epithelium (hOSE) is a cell monolayer that covers the surface of the ovary. Natural events like incessant ovulation, associated reproductive hormone action prior to and post-ovulation, along with the ovulationassociated inflammation, that result in injury and repair of hOSE, are considered to have a role in the development of epithelial ovarian cancer (EOC). Progesterone is apoptotic and anti-inflammatory, whereas androgens appear cytoproliferative for hOSE. Local generation of these steroid hormones is subject to 3β-hydroxysteroid dehydrogenase (3β-HSD) activity. Moreover, action of these hormones is achieved through coupling to their cognate receptors, progesterone (PR) and androgen receptors (AR). The overall aim of this thesis is to elucidate in vitro the regulation of progesterone and androgen biosynthesis and downstream signalling during the injury and repair of primary hOSE cells that were collected from pre-menopausal women who underwent surgery for benign gynaecological disorders. Injury was mimicked by treatment of cells with several pro-inflammatory cytokines, whereas repair was mimicked with T-lymphocyte, ‘anti-inflammatory’ cytokines. Immunohistochemical studies showed immunodetectable 3β-HSD in the human ovarian cell surface of whole ovary and three-week cultured hOSE cells, establishing 3β-HSD expression in vivo and in vitro. Cross-reaction of the 3β-HSD antibody with both enzyme isoforms did not allow investigation of isoform expression pattern. However, mRNA transcriptional studies with isoform specific primers and probe sets for semi-quantitative (sq) and quantitative (q) PCR revealed expression of both isoforms in hOSE cells; 3β-HSD1 mRNA was expressed at higher levels relative to 3β-HSD2 mRNA in accordance with the preference of this isoform in peripheral non-steroidogenic tissues. Of the cytokines tested, only IL-1α and IL-4 affected 3β-HSD expression. IL- 1α suppressed 3β-HSD1 mRNA, whereas it up-regulated 3β-HSD2 mRNA as assessed with qPCR, without though affecting total 3β-HSD protein and activity levels as assessed with western immunoblotting and radiometric activity assays, respectively. IL-1α did not affect AR or PR mRNA levels, suggesting a balance in androgen and progesterone biosynthesis during post-ovulatory wounding. IL-4 massively induced 3β-HSD1 and 3β-HSD2 mRNA and total 3β-HSD protein and activity. It also attenuated AR mRNA and protein, without affecting PR mRNA. Collectively, these data demonstrate that IL-4 sustains progesterone rather than androgen signalling and this may be part of the anti-inflammatory steroid action that protects hOSE from genetic damage. IL-1α effects appear to be mediated by NF-κB signalling pathway. PI-3K and p38 MAPK appeared involved in IL-1α-induced 3β- HSD2. IL-4-induced 3β-HSDs required STAT-6 and PI-3K pathways and also p38 MAPK at the case of 3β-HSD2. IL-4-attenuated AR was reversed by a p38 MAPK inhibitor. These data suggest that steroid signalling by IL-1α and IL-4 involve multiple signalling pathways. In primary EOC, 3β-HSD1 and 3β-HSD2 transcripts were attenuated relative to hOSE cells, suggestive of an acquired feature of neoplastic transformation. However, both transcripts could be restored after IL-4 treatment, attesting a therapeutic advantage of this cytokine. In conclusion, we have shown that 3β-HSD is under inflammatory control during ovarian post-ovulatory wound healing of hOSE. IL-1α- and IL-4-mediated 3β-HSD1 and 3β-HSD2 are regulated by multiple signalling pathways. Also, IL-4 was identified as an anti-inflammatory agent in hOSE with putative therapeutic benefit in malignancy.
3

The Roles of Elevated Bcl-2 in Ovarian Cancer

Anderson, Nicole Shree 13 December 2010 (has links)
Ovarian cancer (OC) is the second most common gynecologic cancer; however it is responsible for the most gynecologic cancer-related deaths. Apoptosis evasion is an important mechanism in OC tumorigenesis, and the prototypic anti-apoptotic protein, B-cell lymphoma 2 (Bcl-2), is often overexpressed in OC tumors. Gaining a better understanding of the mechanism(s) behind Bcl-2 overexpression and potential extra-anti-apoptotic functions of Bcl-2 could elucidate the importance of elevated Bcl-2 in OC. In the current study, I show through immunohistochemical analysis of normal, benign, and OC tissue sections, that both epithelial and stromal Bcl-2 expression decreases with OC progression. However, the number of Bcl-2-positive lymphocyte nests and the size of these lymphocyte nests increase dramatically with OC progression. Additionally, this study shows that lysophosphatidic acid (LPA), a glycerophospholipid frequently elevated in serum and ascites fluid of OC patients, upregulates Bcl-2 in OC cells. Bcl-2 enzyme-linked immunosorbant assay (ELISA), western blot analysis, reverse transcriptase polymerase chain reaction (RT-PCR), and luciferase reporter assays reveal that LPA increases Bcl-2 promoter, messenger RNA (mRNA), and protein levels in OC cells, but not in normal immortalized ovarian surface epithelial (IOSE) cells. LPA also increases secreted levels of Bcl-2. In vitro human umbilical vein endothelial cell (HUVEC) tube formation assays show that OC-derived Bcl-2 or recombinant human (rh) Bcl-2 promotes aberrant formation of tube-like structures. Though extracellular Bcl-2 does not affect HUVEC cell viability, it may cause aberrant tube formation by inhibiting HUVEC migration. Finally, Bcl-2 ELISA reveals that urinary Bcl-2 levels in OC patients are higher than those in normal individuals and patients with benign gynecologic disease. Urinary Bcl-2 also complements serum CA125 when the two are compared in parallel samples. Furthermore, urinary Bcl-2 decreases following cytoreductive surgery. Altogether, the results suggest that Bcl-2 is important in OC tumorigenesis and angiogenesis. Additionally, urinary Bcl-2 may be a valuable non-invasive biomarker for OC diagnosis and/or screening. Consequently, further elucidation of mechanisms of Bcl-2 overexpression and its extra-apoptotic functions could lead to improved treatment and diagnostic strategies for OC patients.
4

Effect of the reproductive cycle on morphology and activity of the ovarian surface epithelium in mammals

Saddick, Salina Yahya January 2010 (has links)
The layer of cells lining the outer surface of the mammalian ovary, the ovarian surface epithelium (OSE), is a constant feature throughout the dynamic tissue remodeling that occurs throughout the reproductive cycle (follicle growth, ovulation, corpora lutea formation and pregnancy). Abnormal development of these cells is responsible for 90% of all epithelial ovarian cancers in women and epidemiological studies have shown that susceptibility to ovarian cancer is negatively correlated with increasing pregnancy. Little is known about how OSE cells are affected at each stage of the cycle, so the main aim of this study was to determine how the reproductive cycle affected proliferation and degeneration of OSE cells. This study utilised three animal models each with a different type of reproductive cycle: a mono-ovular seasonal breeder (Sheep), a mono-ovular polyoestrous breeder (Cow) and a poly-ovular non human primate (marmoset) to allow comparisons to be made. Comparison of OSE proliferative activity was made in sheep and marmoset at each stage of the cycle including pregnancy and anoestrous. The bovine model was used to investigate apoptotic cell death. Proliferative activity of somatic cells within the sheep ovary was monitored throughout the reproductive cycle by detection of cell cycle markers PCNA and Ki67 using immunohistochemistry. The pattern of OSE proliferation was correlated with the pattern of follicle development at each stage (sheep and marmoset). During pregnancy cell proliferation was significantly lower in OSE and in granulosa cells, reflecting a suppression of mature follicle development during these stages whereas in cycling animals proliferation was increased. Differences in OSE proliferation were observed in relation to the local underlying tissue environment in both sheep and marmoset. Epithelial cell rupture and regeneration enhanced the hormonal mitogenic action on epithelial cells, which showed highest proliferation over corpora lutea in each animal model. To test the hypothesis that these changes are mediated by hormones or growth factors ovine OSE cells were cultured and proliferative activity monitored after treatment with several factors: fetal calf serum (FCS), follicular fluid from follicles of varying sizes, corpora lutea extracts, recombinant human IGF-1, oestradiol and progesterone. IGF alone was demonstrated to have an affect on increasing proliferation of cultured OSE cells. Levels of FSHr and LHr were monitored by quantitative real- time PCR and it was demonstrated that the concentration of gonadotrophin receptors in OSE, increased prior to and after ovulation, at which time the in vivo OSE proliferation also peaked. The in situ apoptosis index was determined in bovine tissue using TUNEL throughout the regular cycle, and at mid and late-pregnancy stages. The results showed that pregnancy induced apoptotic activity in OSE cells and up regulated the tumour suppressor gene p53. Cultured bovine OSE cells also exhibited an increased level of apoptosis following progesterone treatment. Since p53/p53 gene expression in OSE over the corpora lutea producing progesterone also increased, this progesterone-mediated apoptosis may be mediated through an up-regulation of p53 synthesis. The effect of pregnancy and low production of gonadotrophins in the regulation of OSE cell morphology and activity was further investigated in the marmoset monkey (a non-human primate) treated with GnRH antagonist and infused with BrdU to monitor proliferative activity. OSE proliferation was correlated to ovarian events (follicular growth, ovulation and luteinization) and this was suppressed during pregnancy. Inhibition of gonadotrophin secretion by treatment with a GnRH antagonist also markedly inhibited OSE proliferation. Taken together these studies support the hypothesis that pregnancy and periods of anovulation reduce proliferation of OSE cells and alter the pattern of apoptotic cell death and that this effect is independent of species and reproductive pattern. Suppression of gonadotrophins and other growth factors during pregnancy could enhance p53-mediated apoptosis of damaged and mitogenic cells arising from repeated ovulations. This effect may partly explain why increasing number of pregnancies in woman reduces the chance of epithelial ovarian cancers.
5

Study of inflammatory signalling in epithelial ovarian cancer and the normal human mesothelium

Fegan, Kenneth Scott January 2010 (has links)
Epithelial Ovarian Cancer (EOC) kills more women annually in the United Kingdom than any other gynaecological cancer. Survival rates for women diagnosed with EOC have not improved over the past 30 years, due to the often advanced stage at presentation, where widespread intra-peritoneal dissemination has occurred. The natural history of the disease remains uncertain but the ovarian surface epithelium (OSE) is a strong candidate for the tissue of origin. The OSE undergoes cyclical damage and repair in women of reproductive age following ovulation, which can be considered an acute inflammatory event. Factors that prevent ovulation (pregnancy, breastfeeding and contraceptive pill use) also protect against the development of EOC. Previously published data show that the OSE is able to upregulate the enzyme 11-beta hydroxysteroid dehydrogenase type 1 (11βHSD1) in response to inflammation, the enzyme responsible for converting inactive cortisone to anti-inflammatory cortisol. This thesis hypothesises that 11βHSD isozymes are deregulated in ovarian cancer; that the peritoneal surface epithelium (PSE) is indistinguishable from the OSE in its response to inflammation and should be considered a potential source of some “ovarian cancers”; and finally that the expression of the tumour suppressor gene OPCML (OPioid binding Cell adhesion Molecule-Like) is altered by inflammation. These hypotheses were examined at three levels. Firstly, primary cultures of EOC were established, and glucocorticoid metabolism and the response to inflammation was compared to normal OSE. Results from these investigations reveal that the11βHSD1 response to IL-1α stimulation is impaired in EOC compared to normal OSE at the mRNA level but there is no significant difference when 11βHSD1 enzyme activity is measured in these tissues. When basal levels of 11βHSD1, 11βHSD2 and COX2 are compared amongst untreated samples of EOC and OSE, there was a significant correlation between 11βHSD1 and COX2 mRNA expression (P<0.001). 11βHSD2 mRNA expression was significantly higher in the EOC specimens compared to OSE (P<0.05). Secondly the response to inflammation was compared in primary cultures of human peritoneal surface epithelial (PSE) cells and OSE. The data suggest that the mRNA response to inflammation was similar in OSE and PSE, but that the 11βHSD1 enzyme activity was reduced in PSE (P<0.05), which may result in differences in tissue healing. Finally, the effect of inflammation on the expression of the ovarian cancer associated tumour suppressor gene (TSG), OPCML (OPioid binding Cell adhesion Molecule-Like) and the other members of the IgLON family, was examined in OSE. These results suggest that OPCML mRNA expression can be induced by IL-1α, an effect that is inhibited by cortisol.
6

The Interrelationship of BRCA1 185delAG, Interleukin-1β, and Ovarian Oncogenesis

Woolery, Kamisha 27 June 2014 (has links)
While the etiology of ovarian cancer (OC) is not completely understood, evidence suggests that chronic inflammation may promote malignant transformation. However, familial history remains the strongest risk factor for developing OC and is associated with germline BRCA1 mutations, such as the 185delAG mutation. Normal human ovarian surface epithelial cells expressing the 185delAG mutant, BRAT, exhibit molecular and pathological changes that may contribute to OC oncogenesis. In the current study, I sought to determine whether BRAT could promote an inflammatory phenotype by investigating BRAT's impact on the expression of the proinflammatory cytokine, Interleukin-1β (IL-1β). Using a culture model system of normal human ovarian surface epithelial (OSE) cells with and without the BRCA1 185delAG frameshift mutation, BRAT, I investigated BRAT's role in IL-1β expression. OSE cells stably expressing the 185delAG mutation and ovarian surface epithelial cells with endogenous 185delAG were analyzed for differential target gene expression by real time PCR, western blot, ELISA, luciferase reporter and siRNA assays. Normal and malignant breast epithelial cell lines transiently expressing BRAT were also evaluated by real time PCR to determine whether BRAT-induced IL-1β expression is tissue specific. BRAT-expressing OSE cells exhibited enhanced IL-1β mRNA and protein expression. However, expression of BRAT in all breast cell lines failed to significantly alter IL-1β expression levels so that BRAT-mediated IL-1β expression promoting a chronic inflammatory phenotype conducive to malignant transformation may be limited to the ovary. Secondly, since OSE cells expressing the BRCA1 185delAG mutation have increased levels of IL-1β that may contribute to malignant transformation, in a pilot study, I sought to assess whether elevated urinary levels of IL-1β are associated with OC as well as compare urinary IL-1β levels with clinical parameters. Urinary and serum levels of IL-1β were analyzed by ELISA and biostatistical analysis from a patient cohort consisting of healthy women (N=10), women with ovarian benign disease (N=23), women with OC (N=32), women with other benign gynecological conditions (N=22), and women with other gynecological cancers (N=6). Urinary IL-1β levels were elevated in patients with ovarian benign disease and a first degree family history of ovarian and/or breast cancer. Urinary IL-1β levels were also correlated with increased body mass index. Urinary and serum IL-1β levels were increased in ovarian benign and OC patient samples supporting the theory of elevated urinary IL-1β being associated with cancer progression. Lastly, I sought to begin early molecular characterization of BRCA1 185delAG to better understand its role in ovarian transformation. I isolated 185delAG protein expressed in E. coli and utilized web tools to analyze the amino acid sequence to determine the molecular and structural characteristics. The study results showed the predicted BRCA1 185delAG protein product is an ordered, self-aggregating, alpha helical protein structurally and molecularly distinct from wild-type BRCA1. The BRCA1 185delAG amino acid sequence contained domains with resemblance to the Peptidase M20 family. Isolation of the BRCA1 185delAG protein product will allow for further protein analysis to better understand its' oncogeneic functions; as well as, elucidate the mechanism of tissue-specific BRAT-mediated IL-1β expression since increased IL-1β expression may represent an early step contributing to OC.
7

Novel Roles for 185delAG Mutant BRCA1 in Ovarian Cancer Pathology

Linger, Rebecca J. 10 November 2010 (has links)
Familial history is the strongest risk factor for developing ovarian cancer (OC), and a significant contributor to breast cancer risk. Most hereditary breast cancers and OCs are associated with mutation of the tumor suppressor Breast and Ovarian Cancer Susceptibility Gene 1 (BRCA1). Studying risk-associated BRCA1 truncation mutations, such as the founder mutation 185delAG, may reveal signaling pathways important in OC etiology. Recent studies have shown novel BRCA1 mutant functions that may contribute to breast and OC initiation and progression independent of the loss of wtBRCA1. Previously, we have found that normal human ovarian surface epithelial (HOSE) cells expressing the 185delAG mutant, BRAT ( BRCA1 185delAG Amino Terminal truncated protein), exhibit enhanced chemosensitivity and up-regulation of the OC-associated serpin, maspin. In the current study, I identify an additional target of the BRAT mutation, matrix metalloprotease 1 (MMP1), a key player in invasion and metastasis. BRAT-expressing HOSE cells exhibit increased MMP1 messenger RNA (mRNA) by real time PCR and protein by Western blotting. Pro-MMP1 levels are also higher in conditioned media of BRAT-expressing cells and HOSE cell lines derived from BRAT mutation carriers. c-Jun is critical for BRAT-mediated MMP1 up-regulation, as siRNA knockdown diminishes MMP1 levels. Luciferase reporter constructs reveal that activator Protein 1 (AP1) sites throughout the distal end of the promoter contribute to BRAT-mediated MMP1 expression, and basal activity is mediated in part by an AP1 site at (-72). Reporters containing a single nucleotide polymorphism (SNP) associated with OC risk and progression yield increased activity that is further enhanced in BRAT cells. Interestingly, BRAT-mediated changes in chemosensitivity and gene regulation are not recapitulated in a normal breast epithelial or breast cancer cell model. This suggests tissue-specific mutant BRCA1 functions may contribute to breast and ovarian tissue specificity of BRCA1 mutation-associated cancer risk and also to differential breast and ovarian cancer risk and penetrance associated with specific mutations. Early molecular and cellular changes such as MMP1 up-regulation in the ovarian surface epithelium of BRCA1 mutation carriers may promote OC initiation and progression and represent a step forward on the continuum of cellular malignancy. Further investigation is warranted, as elucidating these early changes will aid in identification of potential screening and treatment strategies.
8

Defining the Epithelial-to-Mesenchymal Transition and Regulation of Stemness in the Ovarian Surface Epithelium

Carter, Lauren 27 November 2018 (has links)
The ovarian surface epithelium (OSE) is a monolayer of cells surrounding the ovary that is ruptured during ovulation. After ovulation the wound is repaired, however this process, and the mechanisms to maintain OSE homeostasis after the wound is repaired are poorly understood. We have shown the mouse OSE (mOSE) contains a stem cell population that is expanded by Transforming Growth Factor Beta 1 (TGFB1), a factor present in follicular fluid. These data suggest that components in the follicular fluid such as TGFB1 may promote wound repair and OSE homeostasis through maintenance of the OSE stem cell population. Additionally, TGFB1 may promote wound repair through induction of an epithelial-to-mesenchymal transition (EMT) and activation of pro-survival pathways, as seen in other tissues. To elucidate the mechanism for TGFB1-mediated ovulatory wound repair, mOSE cells were treated with TGFB1, which induced an EMT seen with increased Snai1 expression and cell migration. Snai1 overexpression also increased cell migration and sphere formation (a stem cell characteristic). RNA sequencing results suggest this is at least in part through elevated collagen deposition in SNAI1 overexpressing cells. A TGFB signalling targets array identified Cox2 induction following TGFB1 treatment. Constitutive Cox2 expression did not promote an EMT, but enhanced sphere formation and cell survival. Finally, TGFB1 treatment decreased Brca1 expression, which when deleted from mOSE cells also increased sphere formation. RNA sequencing results suggest that Brca1 deletion promotes stemness through activation of the stem cell genes Ly6a and Lgr5. RNA sequencing was also used to compare mOSE cells cultured as monolayers and as spheroids, with and without TGFB1. These results validate our findings that TGFB1 promotes an EMT partially through Snail induction and the upregulation of Cox2. mOSE cells cultured as spheroids acquire a mesenchymal transcriptional profile that is further enhanced with TGFB1 treatment. These data suggest that TGFB1 may promote ovulatory wound repair and maintain OSE homeostasis through the induction of an EMT, maintenance of the stem cell population and activation of a pro-survival pathway. Interestingly, mOSE spheroids also decrease Brca1 expression and upregulate cancer associated genes such as Pax8 and Greb1. The induction of survival pathways, while simultaneously increasing stemness and repressing Brca1 could render cells more susceptible to transformation. This work provides novel insights as to why ovulation is the primary non-hereditary risk factor for ovarian cancer.
9

The Effects of the Female Reproductive Hormones on Ovarian Cancer Initiation and Progression in a Transgenic Mouse Model of the Disease

Laviolette, Laura 03 May 2011 (has links)
Ovarian cancer is thought to be derived from the ovarian surface epithelium (OSE), but it is often diagnosed during the late stages and therefore the events that contribute to the initiation and progression of ovarian cancer are poorly defined. Epidemiological studies have indicated an association between the female reproductive hormones and ovarian cancer etiology, but the direct effects of 17β-estradiol (E2), progesterone (P4), luteinizing hormone (LH) and follicle stimulating hormone (FSH) on disease pathophysiology are not well understood. A novel transgenic mouse model of ovarian cancer was generated that utilized the Cre/loxP system to inducibly express the oncogene SV40 large and small T-Antigen in the OSE. The tgCAG-LS-TAg mice developed poorly differentiated ovarian tumours with metastasis and ascites throughout the peritoneal space. Although P4 had no effect; E2 significantly accelerated disease progression in tgCAG-LS-TAg mice. The early onset of ovarian cancer was likely mediated by E2’s ability to increase the areas of putative preneoplastic lesions in the OSE. E2 also significantly decreased survival time in ovarian cancer cell xenografts. Microarray analysis of the tumours revealed that E2 mainly affects genes involved in angiogenesis and cellular differentiation, proliferation, and migration. These results suggest that E2 acts on the tumour microenvironment in addition to its direct effects on OSE and ovarian cancer cells. In order to examine the role of the gonadotropins in ovarian cancer progression, the tgCAG-LS-TAg mice were treated with 4-vinylcyclohexene-diepoxide (VCD) to induce menopause. Menopause slowed the progression of ovarian cancer due to a change in the histological subtype from poorly differentiated tumours to Sertoli tumours. Using a transgenic mouse model, it was shown that E2 accelerated ovarian cancer progression, while P4 had little effect on the disease. Menopause (elevated levels of LH and FSH) altered the histological subtype of the ovarian tumours in the tgCAG-LS-TAg mouse model. These results emphasize the importance of generating animal models to accurately recapitulate human disease and utilizing these models to develop novel prevention and treatment strategies for women with ovarian cancer.
10

The Effects of the Female Reproductive Hormones on Ovarian Cancer Initiation and Progression in a Transgenic Mouse Model of the Disease

Laviolette, Laura 03 May 2011 (has links)
Ovarian cancer is thought to be derived from the ovarian surface epithelium (OSE), but it is often diagnosed during the late stages and therefore the events that contribute to the initiation and progression of ovarian cancer are poorly defined. Epidemiological studies have indicated an association between the female reproductive hormones and ovarian cancer etiology, but the direct effects of 17β-estradiol (E2), progesterone (P4), luteinizing hormone (LH) and follicle stimulating hormone (FSH) on disease pathophysiology are not well understood. A novel transgenic mouse model of ovarian cancer was generated that utilized the Cre/loxP system to inducibly express the oncogene SV40 large and small T-Antigen in the OSE. The tgCAG-LS-TAg mice developed poorly differentiated ovarian tumours with metastasis and ascites throughout the peritoneal space. Although P4 had no effect; E2 significantly accelerated disease progression in tgCAG-LS-TAg mice. The early onset of ovarian cancer was likely mediated by E2’s ability to increase the areas of putative preneoplastic lesions in the OSE. E2 also significantly decreased survival time in ovarian cancer cell xenografts. Microarray analysis of the tumours revealed that E2 mainly affects genes involved in angiogenesis and cellular differentiation, proliferation, and migration. These results suggest that E2 acts on the tumour microenvironment in addition to its direct effects on OSE and ovarian cancer cells. In order to examine the role of the gonadotropins in ovarian cancer progression, the tgCAG-LS-TAg mice were treated with 4-vinylcyclohexene-diepoxide (VCD) to induce menopause. Menopause slowed the progression of ovarian cancer due to a change in the histological subtype from poorly differentiated tumours to Sertoli tumours. Using a transgenic mouse model, it was shown that E2 accelerated ovarian cancer progression, while P4 had little effect on the disease. Menopause (elevated levels of LH and FSH) altered the histological subtype of the ovarian tumours in the tgCAG-LS-TAg mouse model. These results emphasize the importance of generating animal models to accurately recapitulate human disease and utilizing these models to develop novel prevention and treatment strategies for women with ovarian cancer.

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