High IGFBP2 expression correlates with tumor severity in pediatric rhabdomyosarcoma

Rhabdomyosarcoma (RMS) is the most common childhood sarcoma and is identified as either the embryonal or alveolar (ARMS) subtype. In approximately 75% of cases, ARMSs are characterized by specific chromosomal translocations that involve PAX and FKHR genes. ARMS gene expression signatures vary, depending on the presence or absence of the translocations. Insulin-like growth factor-binding protein 2 (IGFBP2) is strongly overexpressed in translocation-negative RMS. Because IGFBP2 is associated with tumorigenesis, we investigated its functional role in RMS. An analysis of IGFBP2 distribution in RMS cell lines revealed a strong accumulation in the Golgi complex, in which morphological characteristics appeared peculiarly modified. After silencing IGFBP2 expression, our microarray analysis revealed mostly cell cycle and actin cytoskeleton gene modulations. In parallel, IGFBP2-silenced cells showed reduced cell cycle and rates of invasion and decreased seeding in the lungs after tail vein injections in immunodeficient mice. An analysis of IGFBP2 mRNA and protein localization in human tumors showed abnormal protein accumulation in the Golgi complex, mostly in PAX/FKHR-negative RMS. Moreover, an analysis of patients with RMS revealed the presence of conspicuous circulating levels of IGFBP2 proteins in children with highly aggressive RMS tumors. Taken together, our data provide evidence that IGFBP2 contributes to tumor progression and that it could be used as a marker to better classify clinical and biological risks in RMS

Estrogen therapy and risk of breast cancer in postmenopausal women: a case-control study and results of a multivariate analysis.

Objective: Several randomized trials and observational studies show that the use of hormone therapy (HT) increases the risk of breast cancer (BC). The aim of this study was to assess the effects of exposure to both HT and oral contraceptives (OCs) on BC risk in postmenopausal women, all residing in the same metropolitan area. Methods: Data regarding a series of 238 consecutive postmenopausal women with infiltrating ductal carcinoma (cases) and 255 randomly selected age-matched healthy women (controls) were reviewed. Odds ratios for no breast-feeding and HT and OC use were 1.82 (95% CI, 1.20-2.77), 2.49 (95% CI, 1.73-3.58), and 2.06 (95% CI 1.14-3.70), respectively. Results: Four independent variables (years between menarche and menopause, breast-feeding, OC use, and HT use) were included in the final multivariate analysis using logistic regression. The cumulative odds ratio calculated from the observed versus predicted values, obtained using the logistic regression function, was 4.55 (95% CI, 2.13-9.71), whereas the cumulative risk of common exposure to both OCs and HT was 2.77 (95% CI, 1.44-5.32). The logistic model correctly classified 67.5% (95% CI, 63.2-71.5) of cases. The receiver operating characteristic (ROC) curve of the complete logistic function showed a fair area of accuracy (0.77; 95% CI, 0.72-0.81). Conclusions: Our results show that the risk of common exposure to both OCs and HT increases in women with other risk factors. However, several parameters traditionally considered in epidemiological studies do not have the same weight in each local community, suggesting the need to create different models to correctly select the high-risk population

Relationship between oral contraceptive therapy and estrogen receptor status in patients with breast cancer

Breast cancer (BC) is the most common cancer in women, and the hormone receptor status is one of the most important prognostic factors in patients with BC. The aim of this study was to establish whether a relationship exists between the hormone receptor rate and the main classic risk factors in patients with BC. PATIENTS AND METHODS: The data regarding a series of 351 consecutive women (median age 57 years, range 26-85 years) who had undergone curative surgery for primary BC was retrospectively reviewed. Eighty-seven (24.8%) patients used oral contraceptives. According to the duration of OC therapy, the patients were dichotomized into two Groups. Group A: less than 22 months (47 patients, 54%) and Group B: 22 months or more (40 patients, 46%). RESULTS: Final pathology showed 15 (4.3%) pT1a, 62 (17.7%) pT1b, 133 (37.9%) pT1c, 125 (35.6%) pT2, and 16 (4.5%) pT3 BC. There were 286 (81.5%) infiltrating ductal, and 24 (6.8%) infiltrating lobular breast carcinomas. The average estrogen receptor (ER) and progesterone receptor (PgR) rate was 59.7 +/- 32.8 and 54.2 +/- 33.9, respectively. There was no relationship (p = NS) between either ER or PgR and the age of the patients, age at menarche and menopause, number of pregnancies, age at first pregnancy, number of spontaneous abortions, months of breastfeeding and the use of estrogen replacement therapy. As expected, ER and PgR rates correlated significantly (R = 0.78, p < 0.01). The ER rates of groups A and B were 51.7 +/- 35.6% and 68.2 +/- 23.6%, respectively (p = 0.014). No other differences (p = NS) between the groups were found. CONCLUSION: The prolonged use of oral contraceptives may increase the ER rate within the tumor tissue, and thus such therapy should be considered an indirect positive prognostic factor in patients with BC

High IGFBP2 Expression Correlates with Tumor Severity in Pediatric Rhabdomyosarcoma

Rhabdomyosarcoma (RMS) is the most common childhood sarcoma and is identified as either the embryonal or alveolar (ARMS) subtype. In approximately 75% of cases, ARMSs are characterized by specific chromosomal translocations that involve PAX and FKHR genes. ARMS gene expression signatures vary, depending on the presence or absence of the translocations. Insulin-like growth factorbinding protein 2 (IGFBP2) is strongly overexpressed in translocation-negative RMS. Because IGFBP2 is associated with tumorigenesis, we investigated its functional role in RMS. An analysis of IGFBP2 distribution in RMS cell lines revealed a strong accumulation in the Golgi complex, in which morphological characteristics appeared peculiarly modified. After silencing IGFBP2 expression, our microarray analysis revealed mostly cell cycle and actin cytoskeleton gene modulations. In parallel, IGFBP2-silenced cells showed reduced cell cycle and rates of invasion and decreased seeding in the lungs after tail vein injections in immunodeficient mice. An analysis of IGFBP2 mRNA and protein localization in human tumors showed abnormal protein accumulation in the Golgi complex, mostly in PAX/FKHR-negative RMS. Moreover, an analysis of patients with RMS revealed the presence of conspicuous circulating levels of IGFBP2 proteins in children with highly aggressive RMS tumors. Taken together, our data provide evidence that IGFBP2 contributes to tumor progression and that it could be used as a marker to better classify clinical and biological risks in RMS. © 2011 American Society for Investigative Pathology