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Background: The high mortality rate associated with epithelial ovarian carcinoma (EOC) reflects diagnosis commonly at an advanced stage, but improved early detection is hindered by uncertainty as to the histologic origin and early natural history of this malignancy. Methodology/Principal Findings: Here we report combined molecular genetic and morphologic analyses of normal human ovarian tissues and early stage cancers, from both BRCA mutation carriers and the general population, indicating that EOCs frequently arise from dysplastic precursor lesions within epithelial inclusion cysts. In pathologically normal ovaries, molecular evidence of oncogenic stress was observed specifically within epithelial inclusion cysts. To further explore potential very early events in ovarian tumorigenesis, ovarian tissues from women not known to be at high risk for ovarian cancer were subjected to laser catapult microdissection and gene expression profiling. These studies revealed a quasineoplastic expression signature in benign ovarian cystic inclusion epithelium compared to surface epithelium, specifically with respect to genes affecting signal transduction, cell cycle control, and mitotic spindle formation. Consistent with this gene expression profile, a significantly higher cell proliferation index (increased cell proliferation and decreased apoptosis) was observed in histopathologically normal ovarian cystic compared to surface epithelium. Furthermore, aneuploidy was frequently identified in normal ovarian cystic epithelium but not in surface epithelium. Conclusions/Significance: Together, these data indicate that EOC frequently arises in ovarian cystic inclusions, is preceded by an identifiable dysplastic precursor lesion, and that increased cell proliferation, decreased apoptosis, and aneuploidy are likely to represent very early aberrations in ovarian tumorigenesis. [ABSTRACT FROM AUTHOR]

The effect of leptin on the expression of melanin-concentrating hormone (MCH) was investigated in lean and genetically obese Lep[sup ob] /Lep[sup ob] mice. Murine leptin was subcutaneously infused using osmotic minipumps. The treatment period extended to 7 days and the daily dose of leptin delivered was 100 μg/kg of body weight. In situ hybridization was used to assess the effects of leptin infusion on the expression of MCH mRNA. MCH levels in the brain (hypothalamus/thalamus and the remaining part), spleen and testis were measured by radioimmunoassay coupled to HPLC of selected tissue extracts. Leptin significantly reduced final body weight, weight of brown adipose tissue, daily food intake in obese mice but not in lean animals. In obese mice, leptin led to a rapid reduction in food intake which reached statistical significance after only 24 h and which led to a significant reduction in the body weight after 3 days of treatment. Leptin restored the normal circulating levels of glucose and insulin in obese mice. The present results mainly provide evidence for a stimulating effect of leptin infusion on the MCH neuronal system. The hypothalamic/thalamic levels of MCH mRNA and peptide were higher in mice treated with leptin than in mice infused with phosphate-buffered saline. The stimulation of MCH neurons appeared particularly intense in obese mice, in which the effects of leptin infusion led to the reduction in MCH content of neuron fibers and terminals. Leptin did not affect spleen and testis MCH contents. In the light of the acknowledged orexigenic effects of MCH, the results of this study questioned the direct role of MCH in the action of leptin on energy balance. The increase in MCH expression following leptin could occur as a mechanism to compensate the decrease in energy deposition led to by leptin. It may also indicate that MCH mediates the metabolic actions of leptin indirectly or else that leptin influences actions of MCH other than those related to the regulation of energy balance. [ABSTRACT FROM AUTHOR]

Objective. Endometrial cancers associated with tamoxifen exposure potentially represent a unique resource for investigating the molecular mechanisms of estrogen-induced tumorigenesis. The purpose of this study was to test the hypothesis that tamoxifen-associated endometrial carcinomas have a distinct gene expression profile compared to matched cases not associated with this exposure.Methods. Microarray-based expression profiling was performed on a series of tamoxifen-associated (N = 10) and matched sporadic cases (N = 29) of endometrial carcinoma.Results. Supervised class comparison revealed no statistically significant difference between the two groups (P = 0.48). However, unsupervised hierarchical clustering of the entire sample of tumors revealed two groups with extremely diverse molecular profiles that were independent of tamoxifen exposure. Of recognized clinicopathological factors, histologic grade correlated best with these two molecular classes.Conclusions. These data suggest that the molecular profile of tamoxifen-associated endometrial cancers is not different from that of endometrial carcinomas generally, and further, that there exist two highly distinct molecular subtypes of endometrial carcinoma. [Copyright &y& Elsevier]

Abstract: Objective. : It is widely recognized that racial disparity in survival exists between African–American and Caucasian women with endometrial cancer (EC). Differential mutation frequencies in select genes have been postulated to explain these survival differences. The purpose of this study was to test the hypothesis that African–American women with EC have a distinct gene expression profile compared to Caucasian women with EC. Methods. : Microarray-based expression profiling using the Affymetrix U133A oligonucleotide array was performed on a series of ECs from African–American (n = 14) and Caucasian (n = 25). The two groups were matched for possible confounding variables including stage, histologic grade, and subtype. A model-based class comparison analysis was performed to generate a list of differentially expressed genes using a P value of <0.001. Results. : The class comparison analysis of genes differentially expressed by tumors from the two groups revealed 16 genes differentially expressed at P < 0.001, which was not statistically significant (P = 0.68). In addition, hierarchical clustering analysis did not segregate these tumors into two distinct groups based on race. Conclusion. : These data indicate that there is no discernible difference in global gene expression profiles of ECs from African–American and Caucasian women. Thus, racial disparities in clinical outcomes are unlikely to reflect differences in gene expression and may instead be attributable to other epidemiologic, clinical, or pathologic factors. [Copyright &y& Elsevier]