The etiology and prevention of ovarian cancer

Stadel, Bruce V.

doi:10.1016/0002-9378(75)90509-8

Cited by 155 publications

(67 citation statements)

References 8 publications

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“…Because it has been hypothesized that FSH increases the risk of ovarian malignancy and that pregnancies and oral contraceptives protect the ovary by suppressing secretion of such hormones [29], numerous studies have examined the roles of FSH and/or LH in tumorigenesis. These hormones have been shown to stimulate the growth of normal and [35,36].…”

Section: Discussionmentioning

confidence: 99%

Activation of the PI3K/AKT pathway mediates FSH-stimulated VEGF expression in ovarian serous cystadenocarcinoma

et al. 2008

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There is evidence to suggest that follicle-stimulating hormone (FSH) can facilitate the neovascularization of ovarian cancers by increasing vascular endothelial growth factor (VEGF) expression in cancer cells, although the underlying molecular mechanism of this process is not well known. Therefore, we investigated the effect of FSH on VEGF expression in the ovarian cancer cell lines SKOV-3 and ES-2. Treatment with FSH significantly increased VEGF expression in a dose-and time-dependent manner. In addition, FSH treatment enhanced the expression of survivin and hypoxiainducible factor-1 (HIF-1α). Knockdown of survivin or HIF-1α suppressed VEGF expression, but only knockdown of survivin inhibited FSH-stimulated VEGF expression. Pretreatment with LY294002, a phosphoinositide 3-kinase (PI3K)/AKT inhibitor, neutralized the enhanced expression of survivin induced by FSH, but treatment with U0126, a mitogen-activated protein kinase/extracellular signal-regulated kinase inhibitor, had no such effect. We further showed that ovarian serous cystadenocarcinoma samples had much higher incidence of positive AKT and phosphorylated AKT (pAKT) protein staining than did benign ovarian cystadenoma samples (p < 0.01). The 5-year survival rate was only about 15% in patients with ovarian serous cystadenocarcinoma who had AKT and pAKT expression, whereas it was about 80% in those who did not have AKT or pAKT expression. Taken together, these results indicate that FSH increases the expression of VEGF by upregulating the expression of survivin, which is activated by the PI3K/AKT signaling pathway. Understanding the role of the PI3K/AKT pathway in FSH-stimulated expression of survivin and VEGF will be beneficial for evaluating the prognosis for patients with ovarian serous cystadenocarcinoma and for pursuing effective treatment against this disease.

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Section: Discussionmentioning

confidence: 99%

Activation of the PI3K/AKT pathway mediates FSH-stimulated VEGF expression in ovarian serous cystadenocarcinoma

et al. 2008

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“…The decrease in ovarian cancer risk associated with alcohol drinking may be explained by the reduction of gonadotropins among alcohol drinkers (Lagiou et al 2001), although this effect of alcohol intake is still hypothetical (Kato et al 1989;Kushi et al 1999). The association between exposure to high levels of gonadotropins and ovarian cancer risk has been proposed by Stadel (Stadel 1975).…”

Section: Discussionmentioning

confidence: 99%

Smoking, Earlier Menarche and Low Parity as Independent Risk Factors for Gynecologic Cancers in Japanese: A Case-Control Study

Fujita

Tase

Kakugawa

et al. 2008

Tohoku J. Exp. Med.

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During recent decades, the incidence of gynecologic cancers, i.e., cancers of the cervix, endometrium and ovary, has increased in Japan. However, risk factors of gynecologic cancers have not been fully clarified in Japan. To investigate common and site-specific risk factors among gynecologic cancers, we conducted a hospital-based case-control study. The cases, i.e., 151 cervical, 103 endometrial and 141 ovarian cancer cases and the controls (n = 2016) were selected from female patients aged 30 and over, who were admitted to a single hospital in Miyagi Prefecture from 1997 to 2003. Information on reproductive factors, exogenous hormone use, and lifestyles including smoking was collected using a self-administered questionnaire. Smoking was significantly associated with an increased risk of cervical cancer. A dose-response relationship with the number of cigarettes per day was also observed (p for trend = 0.004). Older age at menarche was associated with a decreased risk of endometrial and ovarian cancers. For these cancers, the decreased risk was detected with increasing parity number (endometrium, p for trend = 0.0001; ovary, p = 0.0002). There was no significant association between exogenous hormone use and gynecologic cancer risk. The results indicate that smoking is a major risk factor of cervical cancer. In addition, hormonal factors, which are related to early onset of menarche and low parity, are common risk factors for endometrial and ovarian cancers. The increase in female smokers and the decrease in fertility rate may contribute to the increase in gynecologic cancer incidence in Japan. cervical cancer; endometrial cancer; ovarian cancer; reproductive factors; smoking.Tohoku

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“…One of the predominant theories is a gonadotropin theory that circulating levels of pituitary gonadotropins increase the risk of malignancy and that pregnancies and oral contraceptives protect by suppressing secretion of these hormones (Gardner 1961, Stadel 1975. Based on recent studies, treatments with FSH and LH/hCG seem to result in growth stimulation in normal, immortalized OSE and some ovarian cancer cells in a dose-and time-dependent manner in vitro (Wimalasena et al 1992, Kurbacher et al 1995, Kraemer et al 2001, Ohtani et al 2001, Parrott et al 2001, Syed et al 2001, Choi et al 2002, although there are controversial reports (Wimalasena et al 1991, Venn et al 1995, Ivarsson et al 2001, Tourgeman et al 2002.…”

Section: Discussionmentioning

confidence: 99%

Gonadotropins upregulate the epidermal growth factor receptor through activation of mitogen-activated protein kinases and phosphatidyl-inositol-3-kinase in human ovarian surface epithelial cells

Choi¹

2005

Endocrine Related Cancer

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Gonadotropins, follicle-stimulating hormone (FSH) and luteinizing hormone (LH) have been implicated as probable risk factors in epithelial ovarian carcinomas, most of which are derived from ovarian surface epithelium (OSE). Since epidermal growth factor (EGF) increases the growth of ovarian surface epithelial cells, we determined the effect of gonadotropins on the expression of epidermal growth factor receptor (EGFR). We investigated the basal levels of EGFR mRNA and protein, and the mechanisms involved in the regulation of EGFR at the transcriptional and translational levels by FSH and LH. The immortalized OSE cell lines (IOSE) derived from normal OSE cells by transfecting SV40 T-antigen (IOSE-80 and IOSE-80PC, a post-crisis line) and ovarian cancer cell lines were employed. A significantly lower level of EGFR was observed in both IOSE-80 and IOSE-80PC cells when compared with the ovarian cancer cell lines, OVCAR-3 and SKOV-3. Treatment of IOSE-80PC cells with FSH and LH (10 -7 and 10 -6 g/ml) resulted in a significant increase in EGFR mRNA at 24 h and EGFR protein at 48 h, whereas the treatment with gonadotropins for 24-48 h induced a mild increase in EGFR in OVCAR-3, but not in SKOV-3 cells. In addition, IOSE-80PC cells treated with gonadotropins and EGF (10 nM) exhibited an additive stimulation of mitogenesis. Further, FSH and LH significantly increased activities of various kinases at 5-10 min, and pre-treatments with LY294002 (an inhibitor of PI3K) or PD98059 (an inhibitor of ERK1/2) partially blocked the gonadotropin-induced up-regulation of EGFR in IOSE-80PC cells. We investigated whether the effect of gonadotropins on EGFR mRNA levels is induced by increased transcription and/or by altered mRNA stability. Treatment of IOSE-80PC cells with FSH (10 -7 and 10 -6 g/ml) significantly enhanced the activity of the EGFR promoter (120 and 140% increase, respectively) at 24 h, and treatment with LH (10 -7 g/ml) for 24 h induced an increase in the activity of EGFR promoter (30%) in these cells. On the other hand, LH resulted in a significant increase in EGFR mRNA stability in the decay curves. Taken together, these results suggest that the effect of gonadotropins on the expression of EGFR may affect cell growth via ERK-1/-2 and PI3K pathways in preneoplastic ovarian surface epithelial cells, and that FSH and LH increase EGFR mRNA by different mechanisms. The former increased EGFR gene transcription essentially, whereas the latter mainly enhanced EGFR mRNA stability.

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The etiology and prevention of ovarian cancer

Cited by 155 publications

References 8 publications

Activation of the PI3K/AKT pathway mediates FSH-stimulated VEGF expression in ovarian serous cystadenocarcinoma

Activation of the PI3K/AKT pathway mediates FSH-stimulated VEGF expression in ovarian serous cystadenocarcinoma

Smoking, Earlier Menarche and Low Parity as Independent Risk Factors for Gynecologic Cancers in Japanese: A Case-Control Study

Gonadotropins upregulate the epidermal growth factor receptor through activation of mitogen-activated protein kinases and phosphatidyl-inositol-3-kinase in human ovarian surface epithelial cells

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