Dipartimento di Farmacia e Scienze della Salute e della Nutrizione - Tesi di Dottorato
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Questa collezione raccoglie le Tesi di Dottorato afferenti al Dipartimento di Farmacia e Scienze della Salute e della Nutrizione dell'Università della Calabria.
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Item Effects of erythropoietin and stem cell factor on normal and cancer cells: implication for supportive therapy in oncological patients(2013-10-23) Bartucci,Monica; Andò,Sebastiano; De Maria,RuggieroThe ability of erythropoietin (Epo) to promote the production of red cells is currently exploited to treat chemotherapy-induced anemia. However, the expression of Epo receptor (EpoR) in a variety of cancer cells suggests that Epo-based supportive therapy can negatively affect the clinical outcome. In line with this hypothesis, some clinical trials have questioned the benefit of Epo administration in patients affected by different tumors, including breast cancer. In this study we directly determined the effect of Epo on cancer mammospheres, whose tumorigenic activity was validated through the establishment of xenografts in immunocompromized SCID mice. Our preliminary data showed that EpoR was expressed in both, undifferentiated mammospheres and in differentiated primary breast cancer cells. The presence of Epo increased the expansion and survival of tumor mammospheres and differentiated primary breast cancer cells. More importantly, Epo was able to considerably protect both, differentiated and undifferentiated breast cancer cells, from death induced by many antineoplastic drugs. Accordingly, we observed that Epo increased the expression of its receptor, induced activation of AKT/PKB and MAPKs and increased the expression of Bcl-xL in breast cancer cells. Thus, the use of Epo may promote the survival and growth of tumorigenic breast cancer cells by counteracting the cytotoxic effects of chemotherapy suggesting the need for alternative therapeutic options in cancer patients. In a comprehensive investigation, 81/120 tumor types examined did not yield any sample positive for c-kit expression, suggesting that the use of Stem Cell Factor (SCF) should be safe in many of the most common malignancies. 1 To determine the possible oncogenic effect of SCF, we compared the pro-tumor activity of Epo and SCF on breast cancer, the major cancer type in women. Among this, we tested the potential protective effects of SCF in preventing hematopoietic cell death during chemotherapy in vivo. Our data are showing that Epo increased the expansion and survival of tumor mammospheres and differentiated primary breast cancer cells. More importantly, Epo was able to considerably protect both, differentiated and undifferentiated breast cancer cells, from death induced by many antineoplastic drugs possibly through increased expression of the anti-apoptotic protein Bcl-xL. SCF, on the contrary, can not exert any pro-tumor activity, since the majority of cancer cells tested, particularly breast cancer, resulted negative for c-kit expression. In in vitro experiments performed on primary human erythroid progenitors we found that SCF is able to prevent apoptosis of erythroid progenitors induced by promising new anticancer agents and in vivo SCF restores the density of bone marrow cells to the level of controls in mice treated with Cisplatin or 5-Fluorouracil (5-FU). In peripheral blood analysis we observe an increase in the levels of all mature blood cells upon SCF administration. Therefore, taken together our experiments demonstrate that SCF protects the hematopoietic system from chemotherapy-induced damage in vivo and outline a protocol for a potential clinical application of SCF to prevent chemotherapy-induced cytotoxicity.Item ERalfa reduces breast cancer cell motility upon cell adhesion on fibronectin and collagen IV and regulates alfa5beta1 integrin expression(2013-10-23) Middea,Emilia; Andò,Sebastiano; Sisci,DiegoItem Estrogens modulate the expression of the deleted gene homolog phosphatase and tensin on chromosome 10 (PTEN) in human seminoma cells TCam2(2014-03-11) Guido,Carmela; Andò,Sebastiano; Sisci,DiegoItem Evidences that leptin upregulates E-cadherin expression in breast cancer: effects on tumor growth and progression(2013-07-01) Pellegrino,Michele; Andò,Sebastiano; Mauro,LoredanaItem Evidences that Progesterone Receptor B decreases Estrogen Receptor α gene expression through its interaction to a half-PRE site at Estrogen Receptor alfa gene promoter.(2013-10-23) Zupo,Silvia; Andò,Sebastiano; Lanzino,Marilena; De Amicis,FrancescaItem Expression of the K303R estrogen receptor alfa mulation induces hormonal resistance in breast cancer(2013-10-21) Giordano,Cinzia; Sisci,Diego; Andò,Sebastiano; Catalano,StefaniaItem Farnesoid X Receptor, through the binding wíth Steroidogenic Fuctor I Responsive Element, inhibits uromutase expression in tumor Leydig cells.(2013-10-21) Malivindi,Rocco; Sisci,Diego; Andò,SebastianoItem IGF-1 regulating aromatase expression through SF-1 supports estrogen-dependent tumor Leydig celle proliferation(2013-06-28) Sirianni,Rosa; Pezzi,Vincenzo; Andò,SebastianoItem Insulin Receptor Substrate 1 modulates the transcriptional activity and turnover of Androgen Receptor in breast cancer cells.(2013-10-23) Garofalo,Cecilia; Andò,SebastianoItem P13-kinase/Akt mediates the early increase of aromatase activity induced by estradiol in MCF-7 cells(2013-10-23) Barone,Ines; Andò,SebastianoItem PPARgamma ligand rosiglitazone inhibits cell growth proliferation and induces apoptosis in breast cancer cells(2013-10-24) Gabriele,Sabrina; Andò,Sebastiano; Bonofiglio,DanielaItem Relevance of nuclear IRS-1 in breast cancer(2013-10-23) Morelli,Catia; Andò,Sebastiano; Sisci,DiegoInsulin receptor substrate 1 (IRS-1), one of the major molecules transmitting signals from the insulin and insulin-like growth factor 1 receptors, has been implicated in breast cancer. Recently, data obtained in different cell models, suggested that in addition to its conventional role as a cytoplasmic signal transducer, IRS-1 can function in the nuclear compartment. However, the role of nuclear IRS-1 in breast cancer has never been addressed. Experiments undertaken in our laboratory showed that in estrogen receptor α (ERα)-positive MCF-7 cells 1) a fraction of IRS-1 is translocated to the nucleus upon 17-β-estradiol (E2) treatment; 2) E2-dependent nuclear translocation of IRS-1 is blocked with the antiestrogen ICI 182,780; 3) nuclear IRS-1 colocalizes and coprecipitates with ERα; 4) the nuclear IRS- 1:ERα complex is recruited to the E2-sensitive pS2 gene promoter. Furthermore, transfection reporter assays with E2-sensitive promoters suggested that the presence of IRS-1 modulates ERα activity at estrogen response element (ERE)-containing DNA. Furthermore, since the expression of nuclear IRS-1 in breast cancer biopsies has never been examined, we wanted to assess whether nuclear IRS-1 is present in breast cancer and non-cancer mammary epithelium and if it correlates with other markers, especially ERα. Parallel studies were done for cytoplasmic IRS-1. IRS-1 and ERα expression was assessed by immunohistochemistry. Data were evaluated using Pearson correlation, linear regression, and ROC analysis. Nuclear IRS-1 was expressed at low levels in normal mammary epithelial cells and at higher levels in benign tumors, ductal carcinoma, and lobular carcinoma. Similarly, ERα expression was low in normal cells and benign tumors, but high in ductal and lobular cancer. Nuclear IRS-1 and ERα positively correlated in ductal breast cancer and benign tumors, but were not associated in lobular cancer and normal mammary epithelium. In ductal carcinoma, both nuclear IRS-1 and ERα negatively correlated with tumor grade, size, mitotic index, and lymph node involvement. Cytoplasmic IRS-1 was expressed in all specimens and positively correlated with ERα in ductal cancer. A positive association between nuclear IRS- 1 and ERα is a characteristic for ductal breast cancer and marks a more differentiated, nonmetastatic phenotype. In summary, our data suggest the existence of interactions between IRS-1 and ERα occurring in the nucleus. These interactions might represent a novel aspect of ER/IGF-I crosstalk in breast cancer.