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Capasso I.,G. Pascale | Esposito E.,G. Pascale | Pentimalli F.,Centro Ricerche Oncologiche Mercongliano | Pentimalli F.,Sbarro Health Research Organization | And 16 more authors.
Cancer Biology and Therapy | Year: 2010

Postmenopausal women show the highest incidence of breast cancer in the female population and are often affected by metabolic syndrome. Metabolic syndrome (MS)-characterized by central adiposity, insulin resistance, low serum high-density lipoprotein cholesterol (HDL-C), high serum triglyceride and high blood pressure-seems to be strictly correlated to breast carcinogenesis. We enrolled 777 healthy women and women with breast cancer in our nested casecontrol study to evaluate the association between MS and breast cancer, analyzing anthropometric parameters (weight, height, BMI, waist and hip circumference), blood pressure, serum HDL-C, triglyceride, fasting plasma glucose, insulin, testosterone and uric acid levels and administering a questionnaire about physical activity, food intake, tobacco use, alcohol abuse, personal and familial history of disease. We found an higher prevalence of metabolic syndrome (30%) in postmenopausal breast cancer patients compared to healthy women (19%). None of the individual MS features was strong enough to be considered responsible for breast carcinogenesis alone. However, of the 63 postmenopausal breast cancer cases associated to MS, 30% presented three or more MS features, suggesting that the activation of multiple molecular pathways underlying MS might contribute to tumorigenesis. Our data support the hypothesis that MS may be an indicator of breast cancer risk in postmenopausal women. The unsettlement of the hormonal arrangement in postmenopausal, along with an increase in visceral adiposity, probably favour the hormone-dependent cell proliferation, which drives tumorigenesis. Adjustments in lifestyle with physical activity intensification and healthy diet could represent modifiable factors for the primary prevention of sporadic breast cancer. © 2010 Landes Bioscience.

Roberti A.,Sbarro Health Research Organization | Rizzolio F.,Sbarro Health Research Organization | Lucchetti C.,Sbarro Health Research Organization | De Leval L.,University of Lausanne | Giordano A.,Sbarro Health Research Organization
Cell Cycle | Year: 2011

Burkitt's lymphoma is one of the most aggressive tumors affecting humans. Together with the characteristic chromosomal translocation that constitutively activates the c-Myc oncogene, alterations in cellular tumor suppressor pathways are additionally required in order to allow the cells to overcome anti-oncogenic barriers and proliferate in an uncontrolled manner. The INK4a/ARF locus on chromosome 9p21 is considered a safeguard locus since it encodes the two important tumor suppressor proteins, p14ARF and p16INK4a. By regulating the p53 and Rb pathways p14ARF and p16INK4a respectively act as pro-apoptotic and cell cycle inhibitor proteins. The importance of the INK4a/ARF locus has been well documented in several human tumors as well as in Burkitt's lymphoma. Although the mechanisms responsible for the transcriptional regulation of the INK4a/ARF locus have been thoroughly characterized, less is known about its posttranscriptional control. In this study we found that p16INK4a and p14Arf are concurrently inactivated in a panel of BL cell lines. We demonstrate that along with the epigenetic silencing of the p16INK4a gene, the complete inactivation of the locus is achieved by the improper turnover of INK4/ARF proteins by the ubiquitin-proteasome system (UPS), as the proteasome inhibitor MG-132 blocks p14ARF degradation and induces a dramatic stabilization of the p16INK4a protein. We establish that the simultaneous deregulation of both DNA methylation patterns and the ubiquitin-dependent proteolysis system is required to completely inactive the INK4/ARF locus, opening new prospects for the understanding and treatment of Burkitt's lymphoma. © 2011 Landes Bioscience.

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