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Articles by C Giordano
Total Records ( 4 ) for C Giordano
  I Barone , Y Cui , M. H Herynk , A Corona Rodriguez , C Giordano , J Selever , A Beyer , S Ando and S. A.W. Fuqua

Aromatase inhibitors (AI) are rapidly becoming the first choice for hormonal treatment of estrogen receptor- (ER)–positive breast cancer in postmenopausal women. However, de novo and acquired resistance frequently occurs. We have previously identified a lysine to arginine transition at residue 303 (K303R) in ER in premalignant breast lesions and invasive breast cancers, which confers estrogen hypersensitivity and resistance to tamoxifen treatment. Thus, we questioned whether resistance to AIs could arise in breast cancer cells expressing the ER mutation. As preclinical models to directly test this possibility, we generated K303R-overexpressing MCF-7 cells stably transfected with an aromatase expression vector. Cells were stimulated with the aromatase substrate, androstenedione, with or without the AI anastrozole (Ana). We found that Ana decreased androstenedione-stimulated growth of wild-type cells, whereas K303R-expressing cells were resistant to the inhibitory effect of Ana on growth. We propose that a mechanism of resistance involves an increased binding between the mutant receptor and the p85 regulatory subunit of phosphatidylinositol-3-OH kinase (PI3K), leading to increased PI3K activity and activation of protein kinase B/Akt survival pathways. Inhibition of the selective "addiction" to the PI3K/Akt pathway reversed AI resistance associated with expression of the mutant receptor. Our findings suggest that the K303R ER mutation might be a new predictive marker of response to AIs in mutation-positive breast tumors, and that targeting the PI3K/Akt pathway may be a useful strategy for treating patients with tumors resistant to hormone therapy. [Cancer Res 2009;69(11):4724–32]

  N Wagner , C Jehl Pietri , P Lopez , J Murdaca , C Giordano , C Schwartz , P Gounon , S. N Hatem , P Grimaldi and K. D. Wagner

Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors. PPARβ agonists were suggested as potential drugs for the treatment of metabolic syndrome, but effects of PPARβ activation on cardiac growth and vascularization are unknown. Thus, we investigated the consequences of pharmacological PPARβ activation on the heart and the underlying molecular mechanisms.

Methods and results

Male C57/Bl6 mice were injected with the specific PPARβ agonists GW0742 or GW501516, or vehicle. Cardiomyocyte size and vascularisation were determined at different time points. Expression differences were investigated by quantitative reverse transcriptase–polymerase chain reaction and western blotting. In addition, the effects of PPARβ stimulation were compared with hearts of mice undergoing long-term voluntary exercise or pharmacological PPAR activation. Five hours after GW0742 injection, we detected an enhanced angiogenesis compared with vehicle-injected controls. After 24 h, the heart-to-body weight ratios were higher in mice injected with either GW0742 or GW501516 vs. controls. The increased heart size was due to cardiomyocyte enlargement. No signs of pathological cardiac hypertrophy (i.e. apoptosis, fibrosis, or deteriorated cardiac function) could be detected. The effects are mediated via calcineurin A (CnA) activation as: (i) CnA was upregulated, (ii) GW0742 administration or co-transfection of PPARβ significantly stimulated the activity of the CnA promoter, (iii) PPARβ protein bound directly to the CnA promoter, (iv) the CnA target genes NFATc3, Hif-1, and Cdk 9 were upregulated in response to PPARβ stimulation, and (v) the inhibition of CnA activity by cyclosporine A abolished the hypertrophic and angiogenic responses to PPARβ stimulation.


Our data suggest PPARβ pharmacological activation as a novel approach to increase cardiac vascularization and cardiac muscle mass.

  G Pellegriti , F De Vathaire , C Scollo , M Attard , C Giordano , S Arena , G Dardanoni , F Frasca , P Malandrino , F Vermiglio , D. M Previtera , G D'Azzo , F Trimarchi and R. Vigneri

The steadily increasing incidence of thyroid cancer has been attributed mostly to more sensitive thyroid nodule screening. However, various environmental factors, such as those associated with volcanic areas, cannot be excluded as risk factors. We evaluated thyroid cancer incidence in Sicily, which has a homogenous population and a province (Catania) that includes the Mt Etna volcanic area.


In a register-based epidemiological survey, we collected all incident thyroid cancers in Sicily from January 1, 2002, through December 31, 2004. The age-standardized incidence rate for the world population (ASRw) was calculated and expressed as the number of thyroid cancer diagnoses per 100 000 residents per year. The association of thyroid cancer incidence rate with sex, age, tumor histotype, and various environmental factors was evaluated by modeling the variation of the ASRw. All statistical tests were two-sided.


In 2002–2004, 1950 incident thyroid cancers were identified in Sicily (among women, ASRw = 17.8, 95% confidence interval [CI] = 16.9 to 18.7; and among men, ASRw = 3.7, 95% CI = 3.3 to 4.1). Although the percentage of thyroid cancers that were microcarcinomas (ie, ≤10 mm) and ratio of men to women with thyroid cancer were similar in all nine Sicilian provinces, thyroid cancer incidence was statistically significantly higher in the province of Catania (among women, ASRw = 31.7, 95% CI = 29.1 to 34.3; and among men, ASRw = 6.4, 95% CI = 5.2 to 7.5) than in the rest of Sicily (among women, ASRw = 14.1, 95% CI = 13.2 to 15.0; and among men, ASRw = 3.0, 95% CI = 2.6 to 3.4) (all P values < .001). Incidence of papillary, but not follicular or medullary, cancers was statistically significantly increased in Catania province, and papillary tumors from patients in Catania more frequently carried the BRAF V600E gene mutation (55 [52%] of 106 tumors) than tumors from patients elsewhere in Sicily (68 [33%] of 205 tumors) (relative risk = 1.7, 95% CI = 1.0 to 2.8, P = .02). Cancer incidence was statistically significantly lower in rural areas than in urban areas of Sicily (P = .003). No association with mild iodine deficiency or industrial installations was found. Levels of many elements (including boron, iron, manganese, and vanadium) in the drinking water of Catania province often exceeded maximum admissible concentrations, in contrast to water in the rest of Sicily.


Residents of Catania province with its volcanic region appear to have a higher incidence of papillary thyroid cancer than elsewhere in Sicily.

  S Catalano , I Barone , C Giordano , P Rizza , H Qi , G Gu , R Malivindi , D Bonofiglio and S. Ando

In situ estrogen production by aromatase conversion from androgens plays an important role in breast tumor promotion. Here, we show that 17β-estradiol (E2) can rapidly enhance aromatase enzymatic activity through an increase of aromatase protein phosphorylation in breast cancer cell lines. In vivo labeling experiments and site-directed mutagenesis studies demonstrated that phosphorylation of the 361-tyrosine residue is crucial in the up-regulation of aromatase activity under E2 exposure. Our results demonstrated a direct involvement of nonreceptor tyrosine-kinase c-Src in E2-stimulated aromatase activity because inhibition of its signaling abrogated the up-regulatory effects induced by E2 on aromatase activity as well as phosphorylation of aromatase protein. In addition, from our data it emerges that aromatase is a target of cross talk between growth factor receptors and estrogen receptor signaling. These findings show, for the first time, that tyrosine phosphorylation processes play a key role in the rapid changes induced by E2 in aromatase enzymatic activity, revealing the existence of a short nongenomic autocrine loop between E2 and aromatase in breast cancer cells.

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