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 Estrogen Receptor beta, through Sp1, recruits a corepressor complex to the Estrogen Receptor alpha gene promoter in breast cancer cells(2012) Zito, Domenico; Sisci, Diego; Andò, SebastianoHuman Estrogen receptors alpha (α) and beta (β) are essential components of a complex signal transduction pathway that regulates mammary growth and development. Several studies have reported that normal breast tissues display a relative higher expression of ERβ than ERα, which drastically changes during breast tumorogenesis. Thus, it is reasonable to suggest that a dysregulation of the two estrogen receptor subtypes may induce breast cancer development. However, the molecular mechanisms involved in the potential opposing roles played by the two estrogen receptors on tumor cell growth still needs to be elucidated. In the present study, we have demonstrated that ERβ overexpression in breast cancer cells decreases cell proliferation and down-regulates ERα mRNA and protein content, with a concomitant repression of estrogen-regulated genes. Transient transfection experiments, using a vector containing the human ERα promoter region, showed that elevated levels of ERβ down-regulated basal ERα promoter activity. Furthermore, site-directed mutagenesis and deletion analysis revealed that the proximal GC-rich motifs at −223 and -214 are critical for the ERβ-induced ERα down-regulation in breast cancer cells. This occurred through ERβ-Sp1 proteinprotein interactions within the ERα promoter region and the recruitment of a corepressor complex containing the nuclear receptor corepressor NCoR, accompanied by hypoacetylation of histone H4 and displacement of RNA polymerase II. Silencing of NCoR gene expression by RNA interference reversed the down-regulatory effects of ERβ on ER α gene expression and cell proliferation Collectively, these results suggest a novel mechanism by which overexpression of ERβ, through NCoR, is able to down regulate ERα expression, thus repressing ERα’s main role on breast cancer cell growthItem DAX-1 at the connection between Androgen Receptor and Aromatase: a novel mechanism in the inhibition of estrogen-dependent cancer cell proliferation(2012) Maris, Pamela; Sisci, Diego; Lanzino, MarilenaItem PPARγ ligands as novel agents able to inhibit breast tumor growth and progression(2011) Vizza, Donatella; Sisci, Diego; Bonofiglio, DanielaItem Molecular Mechanisms of FXR-mediated Growth Inhibition in Hormone-dependent Cancers(2011) Panza, Salvatore; Sisci, Diego; Catalano, StefaniaItem <> estrogen receptor α is the key regulator of the bifunctional role of FoxO3a transcription factor in breast cancer motility and invasiveness(2013-12-02) Cesario, Maria Grazia; Sisci, DiegoThe role of the Forkhead box class O (FoxO)3a transcription factor in breast cancer migration and invasion is controversial. Here we show that FoxO3a overexpression decreases motility, invasiveness, and anchorage-independent growth in estrogen receptor α-positive (ERα+) cancer cells while eliciting opposite effects in ERα-silenced cells and in ERα-negative (ERα−) cell lines, demonstrating that the nuclear receptor represents a crucial switch in FoxO3a control of breast cancer cell aggressiveness. In ERα+ cells, FoxO3a-mediated events were paralleled by a significant induction of Caveolin-1 (Cav1), an essential constituent of caveolae negatively associated to tumor invasion and metastasis. Cav1 induction occurs at the transcriptional level through FoxO3a binding to a Forkhead responsive core sequence located at position −305/−299 of the Cav1 promoter. 17β-estradiol (E2) strongly emphasized FoxO3a effects on cell migration and invasion, while ERα and Cav1 silencing were able to reverse them, demonstrating that both proteins are pivotal mediators of these FoxO3a controlled processes. In vivo, an immunohistochemical analysis on tissue sections from patients with ERα+ or ERα− invasive breast cancers or in situ ductal carcinoma showed that nuclear FoxO3a inversely (ERα+) or directly (ERα−) correlated with the invasive phenotype of breast tumors. In conclusion, FoxO3a role in breast cancer motility and invasion depends on ERα status, disclosing a novel aspect of the well-established FoxO3a/ERα interplay. Therefore FoxO3a might become a pursuable target to be suitably exploited in combination therapies either in ERα+ or ERα− breast tumors.Item Inhibition of estrogen-dependent cyclin D1 expression by androgen receptor in MCF-7 breast cancer cell(2007-11-30) Casaburi, Ivan; Andò, SebastianoItem Ruolo del sistema endocannabinoide nei meccanismi di neuroprotezione da 17β-estradiolo in un modello sperimentale di ischemia cerebrale focale(2013-10-28) Mazzei,Cinzia; Bagetta,GiacintoIn questo studio sono stati determinati i livelli endogeni dell’endocannabinoide finora meglio caratterizzato, anandamide (AEA) e l’attività degli enzimi responsabili, rispettivamente, della sua sintesi e degradazione, la NAPE-PLD e la FAAH, nella corteccia e nello striato di ratti sottoposti ad occlusione dell’arteria cerebrale media (MCAo) di 2 ore. È stato osservato che il contenuto di AEA nello striato di ratti sottoposti a MCAo, ma non nella corteccia, era significativamente incrementato (all’incirca di 3 volte rispetto ai ratti controllo, P < 0.01) e questo incremento era accompagnato parallelamente da un aumentata attività della NAPE-PLD (di circa 1.7 volte rispetto ai ratti controllo, P < 0.01) e da una ridotta attività (~ 0.6 volte; P<0.05) ed espressione della FAAH (~0.7 volte; P< 0.05). Questi effetti indotti dalla MCAo venivano ulteriormente potenziati da un ora di riperfusione, mentre il legame dell’AEA al recettore cannabinoide CB1 e al recettore vanilloide TRPV1 non erano influenzati in maniera significativa dall’insulto ischemico. Inoltre, il trattamento con l’antagonista del recettore CB1, SR141716, e non quello con l’agonista R-(+)- WIN55,212-2, ha dimostrato di ridurre significativamente (33%; P<0.05) il volume cerebrale d’infarto dopo 22 ore di riperfusione; mentre la somministrazione di una dose neuroprotettiva di 17β-estradiolo (0.20 mg/kg, i.p.), che era in grado di ridurre il volume d’infarto del 43%, si dimostrava capace anche di ridurre l’effetto dell’ischemia cerebrale sul sistema endocannabinoide in maniera recettore estrogenico dipendente. In conclusione, abbiamo dimostrato che il sistema endocannabinoide è implicato nella fisiopatologia del danno cerebrale tMCAo indotto e che la modulazione farmacologica di questo sistema endogeno da parte dell’estradiolo conferisce neuroprotezione.Item Inhibitionof cyclin D1 expression by androgen receptor in breast cancer cells-identification of a novel androgen response element(2013-10-23) Capparelli,Claudia; Sisci,Diego; Lanzino,MarilenaItem 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 Insulin Receptor Substrate 1 modulates the transcriptional activity and turnover of Androgen Receptor in breast cancer cells.(2013-10-23) Garofalo,Cecilia; Andò,Sebastiano