Search Results

You are looking at 51 - 60 of 395 items for

  • Abstract: Ovar* x
  • Abstract: Anastrazole x
  • Abstract: Fulvestrant x
  • Abstract: Estr* x
  • All content x
Clear All Modify Search
Restricted access

B R Rao and B J Slotman

Abstract

Ovarian cancer has a poor prognosis. At the time of diagnosis, in the majority of cases, the disease has progressed to a stage where intra-abdominal dissemination has already taken place. The pathogenesis of ovarian cancer is still unknown. However, epidemiologic studies have demonstrated that endocrine factors may play an important role. Elevated steroid hormone levels have been detected in ovarian cancer patients. The use of endocrine therapy, frequently consisting of progestins and/or tamoxifen, given on an empirical basis and as a last resort, has shown a modest response rate of 10-15%. About 50% of the tumors are positive for estrogen and progesterone receptors (PR). The PR status is a prognostic indicator, independent of the stage of disease, histology and patient's age. The majority of ovarian cancers (>70%) are positive for androgen receptors. Anti-androgens inhibit the growth of ovarian cancer cells in vitro in a majority of cases tested. Clinical trials to evaluate the efficacy of anti-androgen are recommended.

Endocrine-Related Cancer (1996) 3 309-326

Free access

Ann M Dorward, Kathryn L Shultz, and Wesley G Beamer

The reproductive hormone environment is an important influence upon spontaneous ovarian granulosa cell (GC) tumor development in genetically susceptible (SWR × SWXJ-9) F1 female mice: androgenic support during puberty stimulates tumorigenesis, while exposure to 17β-estradiol (E2) suppresses tumor initiation. We sought to determine whether gonadotropic stimulation was sufficient to initiate GC tumors in a grafted model system, and to determine the potential for dietary isoflavones (genistein and daidzein) as alternatives to E2 for tumor chemoprevention in vivo. Isolated ovaries from pre-pubertal (SWR × SWXJ-9) F1 females were transferred to the kidney capsule of host mice homozygous for the hypogonadal (hpg/hpg) and severe combined immunodeficiency (scid/scid) mutations. CB17; HPG-Prkdc scid Gnrh1 hpg/Bm host mice received either follicle-stimulating hormone (FSH), or a functional analog for LH human chorionic gonadotropin for 2 consecutive weeks, at which time the ovary grafts were examined for evidence of tumor initiation. LH analog administration, but not FSH, initiated GC tumorigenesis in the graft system, suggesting that the LH surge at puberty initiates GC tumor development in genetically susceptible female mice. To assess the chemopreventive potential of phytoestrogens, GC tumor frequency was compared between (SWR × SWXJ-9) F1 females reared on an isoflavone-free diet versus a diet supplemented with 125 μg/g each of the isoflavones daidzein and genistein. It was observed that (SWR × SWXJ-9) F1 females reared on isoflavone-supplemented diet maintained significantly higher GC tumor frequency (22%) than females reared on isoflavone-free diet (11%), and that non-tumor-bearing siblings reared on the isoflavones had significantly increased ovarian weight, indicative of an overall stimulation of the reproductive hormone axis. The stimulation of GC tumorigenesis by isoflavones, which contrasts with the chemopreventive action of E2 (2.5 mg/kg) administration during pubertal maturation, may result from general stimulation of ovarian growth, and the inability of the genistein and daidzein supplements to suppress LH secretion.

Restricted access

M C Pike, J R Daniels, and D V Spicer

Abstract

Epidemiological studies have consistently found that bilateral oophorectomy at a young age substantially reduces breast cancer risk. Such surgical menopause around age 35 has been found to reduce risk by 60 to 75%. A reversible medical oophorectomy using an agent such as a gonadotropin-releasing hormone agonist (GnRHA) should achieve a similar reduction in risk. Although the use of GnRHA alone is unacceptable because of the associated hypoestrogenic side-effects, these can be satisfactorily prevented by add-back low-dose estrogen treatment with intermittent progestin to protect the endometrium. It is estimated that a regimen of GnRHA plus add-back ultra low-dose estrogen and progestin would prevent some two-thirds of current breast cancer if used from age 30. If used from age 20 almost nine out of ten current breast cancer cases would be avoided. If, as is likely, these estimates also apply to women at high genetic risk of breast cancer because of possession of a BRCA1 or BRCA2 gene, their breast cancer risk would be reduced to below that of 'normal' women. The protective effects on ovarian cancer are calculated to be greater than the protective effects on breast cancer. Practical chemoprevention of breast and ovarian cancer using this approach should be possible within 5 years.

Endocrine-Related Cancer (1997) 4 125-133

Free access

Marc T Goodman, Galina Lurie, Pamela J Thompson, Katharine E McDuffie, and Michael E Carney

Although the role of estrogen in the etiology of ovarian cancer is uncertain, there is increasing evidence that hormone replacement therapy is a risk factor for ovarian malignancy. The production of estrogen involves the conversion of androgens via P450 aromatase, encoded by the CYP19A1 gene. Genetic variation in two CYP19A1 single-nucleotide polymorphisms (SNPs), rs749292 and rs727479, has been found to produce 10–20% increases in estrogen levels among postmenopausal women. We tested the hypothesis that these SNPs were associated with the risk of ovarian cancer in a population-based case–control study in Hawaii, including 367 histologically confirmed epithelial ovarian cancer cases and 602 age- and ethnicity-matched controls. The A allele of rs749292 was positively associated with ovarian cancer risk in a codominant model for all races combined (AG versus AA genotype: odds ratio (OR), 1.48 and 95% confidence interval (CI, 1.07–2.04); GG versus AA: OR, 1.87 (CI, 1.24–2.82); P trend=0.002). Similar significant associations of the rs749292 A allele on the risk of ovarian cancer were found among Caucasian and Japanese women. No relation of the rs727479 SNP to ovarian cancer risk was observed overall, although Caucasian women carrying the variant A allele compared with women with an CC genotype had an OR of 2.91 (CI, 1.15–7.37). These data suggest CYP19A1 variants may influence susceptibility to ovarian cancer.

Free access

Anna Konwisorz, Anette Springwald, Martina Haselberger, Regina Goerse, Olaf Ortmann, and Oliver Treeck

ICB-1 chromosome 1 open reading frame 38 (C1orf38) is a human gene initially described by our group to be involved in differentiation processes of cancer cells. Recently, we have reported ICB-1 as a novel estrogen target gene and identified an estrogen response element in its promoter. In this study, we examined the role of ICB-1 in regulation of proliferation of breast and ovarian cancer cells. We knocked down its expression in estrogen-dependent MCF-7 breast cancer cells and hormone-unresponsive SK-OV-3 ovarian cancer cells by stable transfection with a specific shRNA plasmid followed by G-418 selection. Knockdown of ICB-1 enabled a considerable estrogen response of SK-OV-3 cells in terms of proliferation. This transformation of SK-OV-3 cells into an estrogen-responsive phenotype was accompanied by upregulation of estrogen receptor α (ERα) expression and a significant decrease of ERβ expression on the mRNA level. Expression of ERα-dependent genes progesterone receptor, pS2, fibulin 1c, and c-fos was elevated in SK-OV-3 cells stably expressing ICB-1 shRNA. In MCF-7 cells, ICB-1 knockdown exerted similar effects on gene expression, supporting a general role of ICB-1 in estrogen responsiveness. Our data suggest that differentiation-associated gene ICB-1 might exert antagonistic actions on cellular estrogen response, which can result in inhibition of estradiol-triggered proliferation. The molecular mechanisms mediating this inhibitory effect of ICB-1 on estrogen signaling are suggested to be limitation of ERα transcript levels but sustaining high levels of ERβ, reducing both activation of ERα target genes and cellular proliferation. The identification of ICB-1 as a new player in endocrine-related cancer encourages further studies on the significance of this gene in cancer development and therapy.

Free access

M Wijnen, M M van den Heuvel-Eibrink, M Medici, R P Peeters, A J van der Lely, and S J C M M Neggers

Long-term adverse health conditions, including secondary malignant neoplasms, are common in childhood cancer survivors. Although mortality attributable to secondary malignancies declined over the past decades, the risk for developing a solid secondary malignant neoplasm did not. Endocrine-related malignancies are among the most common secondary malignant neoplasms observed in childhood cancer survivors. In this systematic review, we describe risk factors for secondary malignant neoplasms of the breast and thyroid, since these are the most common secondary endocrine-related malignancies in childhood cancer survivors. Radiotherapy is the most important risk factor for secondary breast and thyroid cancer in childhood cancer survivors. Breast cancer risk is especially increased in survivors of Hodgkin lymphoma who received moderate- to high-dosed mantle field irradiation. Recent studies also demonstrated an increased risk after lower-dose irradiation in other radiation fields for other childhood cancer subtypes. Premature ovarian insufficiency may protect against radiation-induced breast cancer. Although evidence is weak, estrogen–progestin replacement therapy does not seem to be associated with an increased breast cancer risk in premature ovarian-insufficient childhood cancer survivors. Radiotherapy involving the thyroid gland increases the risk for secondary differentiated thyroid carcinoma, as well as benign thyroid nodules. Currently available studies on secondary malignant neoplasms in childhood cancer survivors are limited by short follow-up durations and assessed before treatment regimens. In addition, studies on risk-modifying effects of environmental and lifestyle factors are lacking. Risk-modifying effects of premature ovarian insufficiency and estrogen–progestin replacement therapy on radiation-induced breast cancer require further study.

Free access

Silvia Darb-Esfahani, Ralph M Wirtz, Bruno V Sinn, Jan Budczies, Aurelia Noske, Wilko Weichert, Areeg Faggad, Susanne Scharff, Jalid Sehouli, Guelten Oskay-Özcelik, Claudio Zamagni, Pierandrea De Iaco, Andrea Martoni, Manfred Dietel, and Carsten Denkert

Epidemiological and cell culture studies indicate that ovarian carcinoma growth is dependent on estrogen stimulation. However, possibly due to the lack of a reliable biomarker that helps to select patients according to prognostically relevant estrogen receptor (ER) levels, clinical trials using anti-estrogenic therapeutics in ovarian carcinoma have had inconsistent results. Therefore, we tested if ER expression analysis by a quantitative method might be useful in this regard in formalin-fixed paraffin-embedded (FFPE) tissue. In a study group of 114 primary ovarian carcinomas expression of estrogen receptor 1 (ESR1) mRNA was analyzed using a new method for RNA extraction from FFPE tissue that is based on magnetic beads, followed by kinetic PCR. The prognostic impact of ESR1 mRNA expression was investigated and compared to ERα protein expression as determined by immunohistochemistry. In univariate survival analysis the expression level of ESR1 mRNA was a significant positive prognostic factor for patient survival (hazard ratio (HR) 0.230 (confidence interval (CI) 0.102–0.516), P=0.002). ERα protein expression was correlated to ESR1 mRNA expression (P=0.0001); however, ERα protein expression did not provide statistically significant prognostic information. In multivariate analysis, ESR1 mRNA expression emerged as a prognostic factor, independent of stage, grade, residual tumor mass, age, and ERα protein expression (HR 0.227 (CI 0.078–0.656), P=0.006). Our results indicate that the determination of ESR1 levels by kinetic PCR may be superior to immunohistochemical methods in assessment of biologically relevant levels of ER expression in ovarian carcinoma, and is feasible in routinely used FFPE tissue.

Free access

Amanda J M O’Donnell, Kenneth G Macleod, David J Burns, John F Smyth, and Simon P Langdon

Estrogens play a significant role in the development, growth, invasion and metastasis of ovarian tumors. The transcriptional program regulated by 17β-estradiol (E2) in human ovarian cancer cell lines was analyzed using cDNA microarrays containing 1200 cancer-related genes. Twenty-eight transcripts had at least a threefold change in expression in E2-treated PEO1 ovarian carcinoma cells compared with controls. These differences were confirmed by real-time quantitative PCR and shown to be dependent upon the expression of functional estrogen receptor-α (ERα). Consistent with this, these gene expression changes were blocked by the anti-estrogen tamoxifen. The use of ERα- and ERβ-specific ligands allowed molecular dissection of the E2 response and showed that ERα activation was responsible for the observed changes in gene expression, whereas ERβ played no significant role. Inhibition of de novo protein synthesis by cycloheximide was used to distinguish between primary and secondary target genes regulated by E2. Actinomycin D was used to show that changes in gene expression levels induced by E2 were a result of changes in transcription and not due to changes in mRNA stability. The results presented here demonstrate that estrogen-driven growth of epithelial ovarian carcinoma is mediated by activation of ERα-mediated, and not ERβ-mediated, transcription.

Free access

Srilatha Swami, Aruna V Krishnan, Jasmaine Williams, Abhishek Aggarwal, Megan A Albertelli, Ronald L Horst, Brian J Feldman, and David Feldman

Abstract

Obesity is an established risk factor for postmenopausal breast cancer (BCa), insulin resistance, and vitamin D deficiency, and all contribute to increased synthesis of mammary estrogens, the drivers of estrogen receptor-positive (ER+) BCa growth. As both dietary vitamin D and calcitriol treatments inhibit breast estrogen synthesis and signaling, we hypothesized that vitamin D would be especially beneficial in mitigating the adverse effects of obesity on ER+BCa. To assess whether obesity exerted adverse effects on BCa growth and whether vitamin D compounds could reduce these unfavorable effects, we employed a diet-induced obesity (DIO) model in ovariectomized C57BL/6 mice. Breast tumor cells originally from syngeneic Mmtv-Wnt1 transgenic mice were then implanted into the mammary fat pads of lean and obese mice. DIO accelerated the initiation and progression of the mammary tumors. Treatments with either calcitriol or dietary vitamin D reduced the adverse effects of obesity causing a delay in tumor appearance and inhibiting continued tumor growth. Beneficial actions of treatments with vitamin D or calcitriol on BCa and surrounding adipose tissue included repressed Esr1, aromatase, and Cox2 expression; decreased tumor-derived estrogen and PGE2; reduced expression of leptin receptors; and increased adiponectin receptors. We demonstrate that vitamin D treatments decreased insulin resistance, reduced leptin, and increased adiponectin signaling and also regulated the LKB1/AMPK pathway contributing to an overall decrease in local estrogen synthesis in the obese mice. We conclude that calcitriol and dietary vitamin D, acting by multiple interrelated pathways, mitigate obesity-enhanced BCa growth in a postmenopausal setting.

Free access

S A Khan, D Bhandare, and R T Chatterton Jr

Recent developments in breast epithelial sampling techniques (nipple fluid aspiration, ductal lavage, and random fine needle aspiration) provide new opportunities for the acquisition of hormonal and cellular biomarker data in asymptomatic women, and thereby the possibility of developing a unified vision of how the hormonal environment of the breast may interact with the cellular expression of proteins, and with other evolving candidate markers of breast cancer risk. The purpose of this review is to integrate available information regarding cellular and breast fluid biomarkers of hormone action on the breast, to identify candidate biomarkers for studies of breast cancer risk and prevention. These include the estrogen receptors α andβ, markers of proliferative and apoptotic response, and protein markers of estrogen action in breast cells and nipple fluid. Studies of breast hormone levels in nipple aspiration fluid (NAF) show that estrone sulphate is present in large quantities in the normal breast, while the differences in serum ovarian steroids that are seen in pre- and postmenopausal women are blunted in NAF. The variability of several estradiol precursors in NAF over time is relatively small, a useful attribute of potential biomarkers of breast cancer risk, particularly if they are reversible with intervention in Phase 2 prevention trials. These studies are already providing new insights into the hormonal etiology of breast cancer, and should lead to the identification of robust, reversible biomarkers for use in breast cancer prevention studies.