Background: High insulin and insulin-like growth factor-I (IGF-I) levels may be associated with an increased breast cancer risk and/or death. Given the need to identify modifiable factors that decrease insulin, IGF-I, and breast cancer risk and death, we investigated the effects of a 6-month randomized controlled aerobic exercise intervention versus usual care on fasting insulin, IGF-I, and its binding protein (IGFBP-3) in postmenopausal breast cancer survivors. Methods: Seventy-five postmenopausal breast cancer survivors were identified from the Yale-New Haven Hospital Tumor Registry and randomly assigned to an exercise (n = 37) or usual care (n = 38) group. The exercise group participated in 150 minutes per week of moderate-intensity aerobic exercise. The usual care group was instructed to maintain their current physical activity level. A fasting blood sample was collected on

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BACKGROUND.Methylation‐mediated suppression of detoxification, DNA repair, and tumor suppressor genes has been implicated in cancer development and progression. Studies also have indicated that concordant methylation of multiple genes (methylator phenotypes), rather than a single gene, may predict cancer prognosis. The current study was designed to determine whether a methylator phenotype exists in ovarian cancer, whether methylation frequencies differ between malignant ovarian tumors and ovarian tumors with low malignant potential (LMP or borderline), and whether methylation of multiple genes affects patient survival.METHODS.The current study included 234 consecutively diagnosed patients with either LMP (n = 19 patients) or malignant (n = 215 patients) ovarian tumors. DNA samples were extracted from fresh frozen tissues and were analyzed for methylation in the promoter region of 6 genes (p16, breast cancer 1 [BRCA1], insulin‐like growth factor‐binding protein 3 [IGFBP‐3], glutathione S‐transferase π 1 [GSTP1], estrogen receptor‐α [ER‐α], and human MutL homologue 1 [hMLH1]) by using methylation‐specific polymerase chain reaction analysis.RESULTS.The frequencies of methylation in malignant tumors and LMP tumors were 0% and 0% for GSTP1, respectively; 9% and 0% for hMLH1, respectively; 21% and 5% for BRCA1, respectively; 42% and 21% for p16, respectively; 44% and 26% for IGFBP‐3, respectively; and 57% and 42% for ER‐α, respectively. A methylator phenotype was not detected, but a calculated methylation index (MI) that was based on the total number of genes methylated in each tumor was associated with ovarian cancer risk and progression. A higher MI was associated with malignant tumors (odds ratio, 10.11; 95% confidence interval [95% CI], 1.19–85.75) and disease progression (hazards ratio, 6.53; 95% CI, 1.39–30.65).CONCLUSIONS.Although a methylator phenotype was not identified, the current results suggested that methylation of multiple genes may play an important role in ovarian cancer development and progression and may have clinical implications in prognosis. Cancer 2006. © 2006 American Cancer Society.

The authors caution that although MCAT scores, alone and in combination with undergraduate GPA, are good predictors of medical school performance, they are not perfect. The authors encourage future research exploring additional predictor variables, such as diligence, motivation, communication skills, study habits, and other relevant characteristics. Similarly, they indicate that high grades and Step 1 scores are not the only indicators of success in the medical profession and call for studies examining other important qualities, such as integrity, interpersonal skills, capacity for caring, willingness to commit to lifelong learning, and desire to serve in underserved areas.

Insulin-like growth factor-I (IGF-I) is known to be involved in the development and progression of several types of solid tumors including ovarian cancer. IGF-I levels in local tissue is subject to both endocrine and paracrine/autocrine regulation. To investigate which regulation is more importantly involved in IGF-I action in ovarian cancer regarding tumor progression, we analyzed IGF-I mRNA expression (assuming only from paracrine/autocrine regulation) and peptide concentration (subject to both endocrine and paracrine/autocrine regulation) as well as a genetic polymorphism (CA dinucleotide repeats) in 215 epithelial ovarian cancer patients. Genomic DNA, total RNA and cytosol proteins were extracted from fresh tumor samples. Two alternatively spliced IGF-I transcripts (IGF-IA and IGF-IB) were analyzed using real-time PCR. Cytosol levels of free and total IGF-I were measured with enzyme-linked immunosorbent assay. DNA sizing analysis was performed to determine the CA polymorphism. The study showed that the CA polymorphism had a weak influence on IGF-I expression, but no effect on tumor progression. High levels of free, not total, IGF-I peptide were associated with elevated risk of disease progression (HR = 2.06; 95%CI: 1.22-3.50), and the association was independent of clinicopathologic features of the disease. One of the IGF-I transcripts (IGF-IA) had a similar but less significant impact on disease progression. Women with high IGF-I mRNA and peptide were at greater risk for disease progression compared to those with low in both (HR = 2.13; 95%CI: 1.13-3.95). These findings support the notion that IGF-I is involved in ovarian cancer progression and free IGF-I plays a more important role in the disease. The study also suggests that both endocrine and paracrine/autocrine are involved in the regulation of IGF-I activity in ovarian cancer.

Insulin-like growth factor binding protein-3 (IGFBP-3) is a member of the IGFBP family, which regulates the mitogenic and antiapoptotic effects of insulin-like growth factors. Hypermethylation of the IGFBP-3 promoter has been found to suppress its expression. To evaluate the role of IGFBP-3 in ovarian cancer progression, we examined the survival of 235 consecutively selected epithelial ovarian cancer patients in association with IGFBP-3 promoter methylation and IGFBP-3 expression in tumor tissue. IGFBP-3 promoter methylation was analyzed using methylation-specific polymerase chain reaction. Cytosol protein was extracted and measured using a bicinchoninic acid assay; IGFBP-3 was measured by enzyme linked immunosorbent assay. Promoter methylation of the IGFBP-3 gene was detected in 44% (104/235) of patients. IGFBP-3 promoter methylation was associated with disease progression and death after adjusting for clinical and pathologic variables. The association was more evident in patients with early-stage disease: RR = 2.87 (95% CI: 0.78-10.63) for disease progression and RR = 3.94 (95% CI: 0.91-15.78) for death. Tissue levels of IGFBP-3 did not differ by methylation status but were inversely associated with disease stage and residual tumor size. These results suggest that IGFBP-3 promoter methylation may be a useful prognostic marker for disease progression and death in early-stage ovarian cancer.

Purpose: The insulin-like growth factor (IGF) system plays important roles in cancer; blocking IGF signaling has been shown to have therapeutic effects on tumor growth. Many studies have focused on the effect of IGF-I, but few have addressed IGF-II.To assess the role of IGF-II in cancer, we analyzed IGF-II expression in ovarian cancer and examined its association with disease characteristics and prognosis. Experimental Design: Included in the study were 215 patients with primary epithelial ovarian cancer. Fresh tumor specimens were collected during surgery, and the patients were followed for a median of 31 months. Total RNA was extracted from the tumor and analyzed for IGF-II, IGF binding protein 3 (IGFBP-3), and estrogen receptor-a expressions using quantitative reverse transcription PCR. Survival analysis was done to examine the associations of IGF-II with disease progression. Results: IGF-II expression was found to be higher in tumors with poor prognosis; this included tumors with advanced stage, poor differentiation, serous histology, and large residual lesions. Patients with high IGF-II had elevated risk for disease progression and death, although the significance became less evident when the analysis was adjusted for clinical and pathologic variables. IGFBP-3 expression was higher in less aggressive tumors, but was not associated with disease progression. The expression of estrogen receptor-a had no effect on survival. Conclusion:This study found evidence that IGF-II expression is associated with disease progression, suggesting that IGF-II and IGF signaling are potential targets for ovarian cancer treatment. The study also indicates that IGF-II and IGFBP-3 have limited value in prognosis because of their strong associations with disease stage and tumor grade.

Klotho is an anti-aging hormone and is able to suppress the action of IGFs. High IGF activities are associated with cancer risk and tumor progression. Klotho's role in cancer is unknown. To evaluate Klotho expression in ovarian cancer and its association with IGFs and ovarian cancer progression, a clinical follow-up study of 189 ovarian cancer patients was conducted. Patients were recruited from a teaching hospital at University of Turin in Italy. All patients were diagnosed with epithelial ovarian cancer and underwent surgery for the disease. Fresh tumor tissue was collected from each patient during surgery. Patient clinical and pathological information was collected, including patient age at surgery, disease stage, tumor grade, tumor histology, residual tumor size, debulking result, post-operative chemotherapeutic agent, treatment response, follow-up time and survival outcome. Expressions of total and secreted Klotho as well as IGFs in tumor tissue were analyzed using quantitative real-time PCR. Survival analysis was performed to evaluate the association of Klotho expression with the risk of disease progression and death using Cox proportional hazards regression model. High expression of secreted Klotho was associated with increased risk of disease progression and death. These associations were independent of patient clinical and pathological characteristics. Expression of secreted Klotho was positively correlated with the expression of IGF-I and IGFBP-3 but not with IGF-II. In conclusion, Klotho expression is associated with epithelial ovarian cancer progression, and the protein may serve as an independent marker for ovarian cancer prognosis. Klotho's role in cancer warrants further elucidation.