0000000000940644
AUTHOR
Giuseppe Giannini
showing 35 related works from this author
Galectin-3 is a marker of favorable prognosis and a biologically relevant molecule in neuroblastic tumors
2014
Childhood neuroblastic tumors are characterized by heterogeneous clinical courses, ranging from benign ganglioneuroma (GN) to highly lethal neuroblastoma (NB). Although a refined prognostic evaluation and risk stratification of each tumor patient is becoming increasingly essential to personalize treatment options, currently only few biomolecular markers (essentially MYCN amplification, chromosome 11q status and DNA ploidy) are validated for this purpose in neuroblastic tumors. Here we report that Galectin-3 (Gal-3), a β-galactoside-binding lectin involved in multiple biological functions that has already acquired diagnostic relevance in specific clinical settings, is variably expressed in m…
Human Papilloma Virus-Dependent HMGA1 Expression Is a Relevant Step in Cervical Carcinogenesis
2008
HMGA1 is a member of a small family of architectural transcription factors involved in the coordinate assembly of multiprotein complexes referred to as enhanceosomes. In addition to their role in cell proliferation, differentiation, and development, high-mobility group proteins of the A type (HMGA) family members behave as transforming protoncogenes either in vitro or in animal models. Recent reports indicated that HMGA1 might counteract p53 pathway and provided an interesting hint on the mechanisms determining HMGA's transforming potential. HMGA1 expression is deregulated in a very large array of human tumors, including cervical cancer, but very limited information is available on the mole…
Galectin-3 Impairment of MYCN-Dependent Apoptosis-Sensitive Phenotype Is Antagonized by Nutlin-3 in Neuroblastoma Cells
2012
MYCN amplification occurs in about 20-25% of human neuroblastomas and characterizes the majority of the high-risk cases, which display less than 50% prolonged survival rate despite intense multimodal treatment. Somehow paradoxically, MYCN also sensitizes neuroblastoma cells to apoptosis, understanding the molecular mechanisms of which might be relevant for the therapy of MYCN amplified neuroblastoma. We recently reported that the apoptosis-sensitive phenotype induced by MYCN is linked to stabilization of p53 and its proapoptotic kinase HIPK2. In MYCN primed neuroblastoma cells, further activation of both HIPK2 and p53 by Nutlin-3 leads to massive apoptosis in vitro and to tumor shrinkage an…
Molecular mechanisms of MYCN-dependent apoptosis and the MDM2-p53 pathway: an Achille’s heel to be exploited for the therapy of MYCN amplified neurob…
2012
The p53 oncosuppressor is very seldom mutated in neuroblastoma, but several mecha- nisms cooperate to its functional inactivation in this tumor. Increased MDM2 levels, due to genetic amplification or constitutive inhibition of p14ARF, significantly contribute to this event highlighting p53 reactivation as an attractive perspective for neuroblastoma treat- ment. In addition to its role in tumorigenesis, MYCN sensitizes untransformed and cancer cells to apoptosis. This is associated to a fine modulation of the MDM2-p53 pathway Indeed MYCN induces p53 and MDM2 transcription, and, by evoking a DNA damage response (DDR), it stabilizes p53 and its proapoptotic kinase Homeodomain Interacting Prote…
Studies on the apoptotic activity of natural and synthetic retinoids: discovery of a new class of synthetic terphenyls that potently support cell gro…
2005
New terphenyl derivatives have been synthesized and tested for their effect on cell survival in serum-free cultures. These compounds protected HL60 cells from death and supported their growth with an activity higher than that of the natural 14-hydroxy-retro-retinol. Terphenyls 26 and 28 also possess antiapoptotic activity on neuronal cells, proving them as possible candidates for the treatment of neurodegenerative and ischemic diseases.
Insight into genetic susceptibility to male breast cancer by multigene panel testing: results from a multicenter study in Italy
2019
Breast cancer (BC) in men is rare and genetic predisposition is likely to play a relevant role in its etiology. Inherited mutations in BRCA1/2 account for about 13% of all cases and additional genes that may contribute to the missing heritability need to be investigated. In our study, a well-characterized series of 523 male BC (MBC) patients from the Italian multicenter study on MBC, enriched for non-BRCA1/2 MBC cases, was screened by a multigene custom panel of 50 cancer-associated genes. The main clinical-pathologic characteristics of MBC in pathogenic variant carriers and non-carriers were also compared. BRCA1/2 pathogenic variants were detected in twenty patients, thus, a total of 503 n…
Clinical and pathologic characteristics of BRCA-positive and BRCA-negative male breast cancer patients: results from a collaborative multicenter stud…
2012
Recently, the number of studies on male breast cancer (MBC) has been increasing. However, as MBC is a rare disease there are difficulties to undertake studies to identify specific MBC subgroups. At present, it is still largely unknown whether BRCA-related breast cancer (BC) in men may display specific characteristics as it is for BRCA-related BC in women. To investigate the clinical–pathologic features of MBC in association with BRCA mutations we established a collaborative Italian Multicenter Study on MBC with the aim to recruit a large series of MBCs. A total of 382 MBCs, including 50 BRCA carriers, were collected from ten Italian Investigation Centres covering the whole country. In MBC p…
Kinetic analysis and molecular modeling of the inhibition mechanism of roneparstat (SST0001) on human heparanase
2016
Heparanase is a β-d-glucuronidase which cleaves heparan sulfate chains in the extracellular matrix and on cellular membranes. A dysregulated heparanase activity is intimately associated with cell invasion, tumor metastasis and angiogenesis, making heparanase an attractive target for the development of anticancer therapies. SST0001 (roneparstat; Sigma-Tau Research Switzerland S.A.) is a non-anticoagulant 100% N-acetylated and glycol-split heparin acting as a potent heparanase inhibitor, currently in phase I in advanced multiple myeloma. Herein, the kinetics of heparanase inhibition by roneparstat is reported. The analysis of dose-inhibition curves confirmed the high potency of roneparstat (I…
Association of low-penetrance alleles with male breast cancer risk and clinicopathological characteristics: results from a multicenter study in Italy
2013
It is well-known that male breast cancer (MBC) susceptibility is mainly due to high-penetrance BRCA1/2 mutations. Here, we investigated whether common low-penetrance breast cancer (BC) susceptibility alleles may influence MBC risk in Italian population and whether variant alleles may be associated with specific clinicopathological features of MBCs. In the frame of the Italian Multicenter Study on MBC, we genotyped 413 MBCs and 745 age-matched male controls at 9 SNPs annotating known BC susceptibility loci. By multivariate logistic regression models, we found a significant increased MBC risk for 3 SNPs, in particular, with codominant models, for rs2046210/ESR1 (OR = 1.71; 95 % CI: 1.43–2.05;…
MYCN sensitizes human neuroblastoma to apoptosis by HIPK2 activation through a DNA damage response.
2010
Abstract MYCN amplification occurs in approximately 20% of human neuroblastomas and is associated with early tumor progression and poor outcome, despite intensive multimodal treatment. However, MYCN overexpression also sensitizes neuroblastoma cells to apoptosis. Thus, uncovering the molecular mechanisms linking MYCN to apoptosis might contribute to designing more efficient therapies for MYCN-amplified tumors. Here we show that MYCN-dependent sensitization to apoptosis requires activation of p53 and its phosphorylation at serine 46. The p53S46 kinase HIPK2 accumulates on MYCN expression, and its depletion by RNA interference impairs p53S46 phosphorylation and apoptosis. Remarkably, MYCN ind…
Epigenetic siRNA and Chemical Screens Identify SETD8 Inhibition as a Therapeutic Strategy for p53 Activation in High-Risk Neuroblastoma
2017
Given the paucity of druggable mutations in high-risk neuroblastoma (NB), we undertook chromatin-focused small interfering RNA and chemical screens to uncover epigenetic regulators critical for the differentiation block in high-risk NB. High-content Opera imaging identified 53 genes whose loss of expression led to a decrease in NB cell proliferation and 16 also induced differentiation. From these, the secondary chemical screen identified SETD8, the H4K20me1 methyltransferase, as a druggable NB target. Functional studies revealed that SETD8 ablation rescued the pro-apoptotic and cell-cycle arrest functions of p53 by decreasing p53K382me1, leading to activation of the p53 canonical pathway. I…
BRCA1/BRCA2 rearrangements and CHEK2 common mutations are infrequent in Italian male breast cancer cases
2008
Male breast cancer (MBC) is a rare and poorly known disease. Germ-line mutations of BRCA2 and, to lesser extent, BRCA1 genes are the highest risk factors associated with MBC. Interestingly, BRCA2 germ-line rearrangements have been described in high-risk breast/ovarian cancer families which included at least one MBC case. Germ-line mutations of CHEK2 gene have been also implicated in inherited MBC predisposition. The CHEK2 1100delC mutation has been shown to increase the risk of breast cancer in men lacking BRCA1/BRCA2 mutations. Intriguingly, two other CHEK2 mutations (IVS2+1G>A and I157T) and a CHEK2 large genomic deletion (del9-10) have been associated with an elevated risk for prostate c…
Identification and Characterization of BRCA1 and BRCA2 Founder Mutations
2012
A large number of cancer predisposing BRCA1/BRCA2 mutations have been reported, with a wide variety among populations. In some restricted groups, specific germline mutations in these tumor suppressor genes have been found with high predominance, due to a founder effect. We focused our review on the Italian founder mutations. The first Italian BRCA1 founder mutation, 5083del19, was found in Calabria: the presence of common allele in all carriers of this mutation (also in families with Calabrian origin living in other parts of Italy) confirmed its founder effect. The same BRCA1 mutation was identified in the Sicilian population, but only the haplotype analysis can reveal the common ancestor o…
Multiple independent variants at the TERT locus are associated with telomere length and risks of breast and ovarian cancer
2013
Journal article TERT-locus SNPs and leukocyte telomere measures are reportedly associated with risks of multiple cancers. Using the Illumina custom genotyping array iCOGs, we analyzed ~480 SNPs at the TERT locus in breast (n = 103,991), ovarian (n = 39,774) and BRCA1 mutation carrier (n = 11,705) cancer cases and controls. Leukocyte telomere measurements were also available for 53,724 participants. Most associations cluster into three independent peaks. The minor allele at the peak 1 SNP rs2736108 associates with longer telomeres (P = 5.8 × 10!-7), lower risks for estrogen receptor (ER)-negative (P = 1.0 × 10!-8) and BRCA1 mutation carrier (P = 1.1 × 10!-5) breast cancers and altered promot…
4,5,6,7-Tetrahydro-isoxazolo-[4,5-c]-pyridines as a new class of cytotoxic Hsp90 inhibitors.
2014
Hsp90 is considered an interesting therapeutic target for anticancer drug development. Here we describe a new class of 4,5,6,7-tetrahydro-isoxazolo-[4,5-c]-pyridine compounds. A small library of derivatives has been synthesized and investigated. Some reported compounds show interesting properties combining both notable binding to Hsp90 and potent cell growth inhibitory activity. N-5 substitution with a 2,4 resorcinol carboxamide appears crucial for activity. Moreover, a derivative bearing a hydroxamic acid residue bound to C-3 amide portion was found to inhibit both Hsp90 and HDAC6.
Association of SULT1A1 Arg213His polymorphism with male breast cancer risk: results from a multicenter study in Italy
2014
Male breast cancer (MBC) is rare and poorly understood. Like female breast cancer (FBC), MBCs are highly sensitive to hormonal changes, and hyperestrogenism, specifically, represents a major risk factor for MBC. MBC is considered similar to late-onset, post-menopausal estrogen/progesteron receptors positive FBC (ER+/PR+). Sulfotransferase 1A1 (SULT1A1) is an enzyme involved in the metabolism of estrogens. Recently, SULT1A1 common functional polymorphism Arg213His (638G>A) variant has been found to be associated with increased breast cancer (BC) risk, particularly in post-menopausal women. For this reason, we decided to explore whether SULT1A1 Arg213His could exert an effect on MBC developme…
Whole-exome sequencing and targeted gene sequencing provide insights into the role ofPALB2as a male breast cancer susceptibility gene
2016
BACKGROUND Male breast cancer (MBC) is a rare disease whose etiology appears to be largely associated with genetic factors. BRCA1 and BRCA2 mutations account for about 10% of all MBC cases. Thus, a fraction of MBC cases are expected to be due to genetic factors not yet identified. To further explain the genetic susceptibility for MBC, whole-exome sequencing (WES) and targeted gene sequencing were applied to high-risk, BRCA1/2 mutation–negative MBC cases. METHODS Germ-line DNA of 1 male and 2 female BRCA1/2 mutation–negative breast cancer (BC) cases from a pedigree showing a first-degree family history of MBC was analyzed with WES. Targeted gene sequencing for the validation of WES results w…
The MRN complex is transcriptionally regulated by MYCN during neural cell proliferation to control replication stress
2015
The MRE11/RAD50/NBS1 (MRN) complex is a major sensor of DNA double strand breaks, whose role in controlling faithful DNA replication and preventing replication stress is also emerging. Inactivation of the MRN complex invariably leads to developmental and/or degenerative neuronal defects, the pathogenesis of which still remains poorly understood. In particular, NBS1 gene mutations are associated with microcephaly and strongly impaired cerebellar development, both in humans and in the mouse model. These phenotypes strikingly overlap those induced by inactivation of MYCN, an essential promoter of the expansion of neuronal stem and progenitor cells, suggesting that MYCN and the MRN complex migh…
Heterocyclic and Phenyl Double-Bond-Locked Combretastatin Analogues Possessing Potent Apoptosis-inducing activity in HL60 and in MDR Cell lines
2005
Two new series of combretastatin (CA-4) analogues have been prepared. The alkenyl motif of CA-4 was replaced either by a five-membered heterocyclic (isoxazoline or isoxazole) or by a six-membered ring (pyridine or benzene). The new compounds have been evaluated for their effects on tubulin assembly and for cytotoxic and apoptotic activities. Five compounds (18b, 20a, 21a, 34b, and 35b) demonstrated an attractive profile of cytotoxicity (IC501 microM) and apoptosis-inducing activity but poor antitubulin activity. The isoxazoline derivatives 18b, 20a, and 21a, demonstrated potent apoptotic activity different from that of natural CA-4. Their ability to block most cells in the G2 phase suggests…
Novel and known genetic variants for male breast cancer risk at 8q24.21, 9p21.3, 11q13.3 and 14q24.1: Results from a multicenter study in Italy
2015
Increasing evidence indicates that common genetic variants may contribute to the heritable risk of breast cancer (BC). In this study, we investigated whether single nucleotide polymorphisms (SNPs), within the 8q24.21 multi-cancer susceptibility region and within BC-associated loci widespread in the genome, may influence the risk of BC in men, and whether they may be associated with specific clinical-pathologic characteristics of male BC (MBC). In the frame of the ongoing Italian Multicenter Study on MBC, we performed a case-control study on 386 MBC cases, including 50 BRCA1/2 mutation carriers, and 1105 healthy male controls, including 197 unaffected BRCA1/2 mutation carriers. All 1491 subj…
A convenient synthesis of unsymmetrically substituted terphenyls of biologically active stilbenes via a double Suzuki cross-coupling protocol
2003
A double Suzuki cross-coupling protocol has been devised as a practical route to a variety of terphenyls. Good chemoselectivity was observed. Unsymmetrically substituted triphenylenes were also easily prepared.
Additional file 5: of Male breast cancer in BRCA1 and BRCA2 mutation carriers: pathology data from the Consortium of Investigators of Modifiers of BR…
2016
Pathology of invasive BRCA1 female and male breast tumours and ORs in predicting male BRCA1 mutation carrier status. (DOCX 19 kb)
Additional file 1: of Male breast cancer in BRCA1 and BRCA2 mutation carriers: pathology data from the Consortium of Investigators of Modifiers of BR…
2016
Male BRCA1 and BRCA2 mutation carriers by study group/country. (DOCX 21 kb)
Additional file 4: of Male breast cancer in BRCA1 and BRCA2 mutation carriers: pathology data from the Consortium of Investigators of Modifiers of BR…
2016
Pathology of BRCA1 and BRCA2 MBCs and ORs in predicting BRCA2 mutation carrier status. (DOCX 20 kb)
Additional file 3: of Male breast cancer in BRCA1 and BRCA2 mutation carriers: pathology data from the Consortium of Investigators of Modifiers of BR…
2016
Methods and thresholds used to define the final marker variables for study groups providing MBC cases. (DOCX 20 kb)
Associations of common breast cancer susceptibility alleles with risk of breast cancer subtypes in BRCA1 and BRCA2 mutation carriers
2014
Introduction More than 70 common alleles are known to be involved in breast cancer (BC) susceptibility, and several exhibit significant heterogeneity in their associations with different BC subtypes. Although there are differences in the association patterns between BRCA1 and BRCA2 mutation carriers and the general population for several loci, no study has comprehensively evaluated the associations of all known BC susceptibility alleles with risk of BC subtypes in BRCA1 and BRCA2 carriers. Methods We used data from 15,252 BRCA1 and 8,211 BRCA2 carriers to analyze the associations between approximately 200,000 genetic variants on the iCOGS array and risk of BC subtypes defined by estrogen re…
Additional file 2: of Male breast cancer in BRCA1 and BRCA2 mutation carriers: pathology data from the Consortium of Investigators of Modifiers of BR…
2016
List of local ethics committees that granted approval for the access and use of the data in present study. (DOCX 23 kb)
Additional file 6: of Male breast cancer in BRCA1 and BRCA2 mutation carriers: pathology data from the Consortium of Investigators of Modifiers of BR…
2016
Pathology of invasive MBCs in the general population from SEER and BRCA1 MBCs and ORs in predicting male BRCA1 mutation carrier status. (DOCX 19 kb)
Additional file 3: of Male breast cancer in BRCA1 and BRCA2 mutation carriers: pathology data from the Consortium of Investigators of Modifiers of BR…
2016
Methods and thresholds used to define the final marker variables for study groups providing MBC cases. (DOCX 20 kb)
Additional file 2: of Male breast cancer in BRCA1 and BRCA2 mutation carriers: pathology data from the Consortium of Investigators of Modifiers of BR…
2016
List of local ethics committees that granted approval for the access and use of the data in present study. (DOCX 23 kb)
Additional file 1: of Male breast cancer in BRCA1 and BRCA2 mutation carriers: pathology data from the Consortium of Investigators of Modifiers of BR…
2016
Male BRCA1 and BRCA2 mutation carriers by study group/country. (DOCX 21 kb)
Additional file 4: of Male breast cancer in BRCA1 and BRCA2 mutation carriers: pathology data from the Consortium of Investigators of Modifiers of BR…
2016
Pathology of BRCA1 and BRCA2 MBCs and ORs in predicting BRCA2 mutation carrier status. (DOCX 20 kb)
Evaluation of CYP17A1 and CYP1B1 polymorphisms in male breast cancer risk
2019
Breast cancer in men is a rare and still poorly characterized disease. Inherited mutations in BRCA1, BRCA2 and PALB2 genes, as well as common polymorphisms, play a role in male breast cancer genetic predisposition. Male breast cancer is considered a hormone-dependent tumor specifically related to hyperestrogenism. Polymorphisms in genes involved in estrogen biosynthesis and metabolism pathways, such as CYP17A1 and CYP1B1, have been associated with breast cancer risk. Here, we aimed to investigate the role of CYP17A1 and CYP1B1 polymorphisms in male breast cancer risk. A series of 597 male breast cancer cases and 1022 male controls, recruited within the Italian Multicenter Study on male brea…
Additional file 5: of Male breast cancer in BRCA1 and BRCA2 mutation carriers: pathology data from the Consortium of Investigators of Modifiers of BR…
2016
Pathology of invasive BRCA1 female and male breast tumours and ORs in predicting male BRCA1 mutation carrier status. (DOCX 19 kb)
Additional file 6: of Male breast cancer in BRCA1 and BRCA2 mutation carriers: pathology data from the Consortium of Investigators of Modifiers of BR…
2016
Pathology of invasive MBCs in the general population from SEER and BRCA1 MBCs and ORs in predicting male BRCA1 mutation carrier status. (DOCX 19 kb)