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Epigenetics & Genetics Program

Research in Dr. Macaluso’s laboratory covers three main topics relating to the role of pRb family proteins in Breast Cancer, Lung Cancer and Healthy Vision.

Program Details | Biography Details | Publications

  EPIGENETIC AND GENETIC

PROGRAM DETAILS

The pRb family proteins (pRb1/105, p107, pRb2/p130), collectively referred to as pocket proteins, are believed to function primarily as regulators of the mammalian cell cycle progression, and suppressors of cellular growth and proliferation. In addition, different studies suggest that these pocket proteins are also involved in development and differentiation of various tissues and, more recently, a broad range of evidence indicates that pRb-family proteins associate with a wide variety of transcription factors and chromatin remodeling enzymes forming transcriptional repressor complexes that control gene expression.

For several years our research group has focused on understanding the molecular mechanisms underlying epigenetic and genetic alteration in human cells leading to cancer formation and progression. Our specific research has concentrated on the mechanisms regulated by pRb-family proteins and governing the neoplastic processes. Our interest is to carry out the complex network of signals by which this family of proteins regulates cellular proliferation, survival and differentiation, and to disclose the mechanisms responsible for the regulatory disruption of these functions in the neoplastic process.

In this context, we have suggested that the silencing of estrogen receptor alpha (ER-α) gene during breast cancer progression, as well as of p73 gene in osteosarcoma, could arise from epigenetic events mediated by pRb2/130 (and perhaps by pRb1/105 and p107) in association with specific enzymes involved in the chromatin remodeling. Furthermore, our work has shown that epigenetic mechanisms controlled by pRb2/p130, as well as epigenetic events affecting Rb2/130 gene expression itself, play an important role in retinoblastoma and lung cancer formation and progression, and can represent key events in the differentiation of cornea and conjunctiva normal cells.

Our research divides into three main topics.

The role of pRb family proteins in breast cancer formation and progression and interaction of pRb family proteins with chromatin modifying enzymes.

Specific projects research:
• pRb family proteins (in particular pRb2/p130) and regulation of estrogen receptors (alpha and beta) gene expression by chromatin remodeling in breast cancer.
• Development of new protocols for cancer treatment by induction of estrogen receptors expression (estrogen receptor alpha and beta) through the design of new anticancer molecules
• Development of new protocols for the identification of subgroups of patients at a higher risk of relapse and death who would benefit from particular therapeutic choices, more aggressive treatment forms, and more specific follow-up modulations.

We also investigate the role of pRb family proteins in modulating PAI-2 (plasminogen activator inhibitor type-2 gene expression by chromatin remodeling, in normal corneal and conjunctival cells.

Specific projects include:
• Cross talk between pRb family members and PAI-2 protein during the differentiation of corneal and conjunctival cells.
• Development of new strategy for the treatment of chronic and acute inflammation of eye and maintenance health vision.

The lab also investigates the role of pRb family proteins in lung cancer formation and progression. Specifically we are looking at:
• Genetic and epigenetic (Rb family gene methylation ) alterations in lung cancer
• Development of new strategies for lung cancer treatment through gene therapy approaches and design of new anticancer molecules.

Epigenetic regulation of ER-α by pRb2/p130 in breast cancer
The molecular mechanism governing estrogen receptor-α (ER-α) transcriptional activity and/or silencing by chromatin remodeling in breast cancer cells is still unclear. However, we showed that the presence of specific pRb2/p130-macromolecular complexes strongly correlate with the methylation status of ER- α gene. Furthermore, we suggested that pRb2/p130 could cooperate with ICBP90 (Inverted CCAAT box Binding Protein of 90 kDa) and DNMTs (DNA methyl transferase) in maintaining a specific methylation pattern of ER-α gene in breast cancer cells. Our novel and intriguing hypothesis is that the sequence of epigenetic events for establishing and maintaining the silenced state of ER-α gene can be locus or pathway specific, and that the remodeling of local chromatin structure of ER-α gene by pRb2/p130-multimolecular complexes may influence its susceptibility to specific DNA methylation. Our data could provide a basis for understanding how the complex pattern of ER-α methylation and transcriptional silencing are generated, and for understanding the relationship between this pattern and its function during the neoplastic process. Moreover, our results may provide a key to understanding the mechanism regulating ER-α expression during the neoplastic events and then provide a then to provide new targets for designing novel therapeutic strategies.

Hypothetical model of how pRb2/p130-complexes may regulate ER-α transcription
A, pRb2/p130-corepressor complex repress the ER-α transcription by maintaining a close chromatin conformation in MDA-MB-231 cells. The interaction between the pRb2/p130-complex and ICBP90 leads to the recruitment of DNMT1 and concomitant release of p300. Histone deacetylation and methylation, perhaps ubiquitination of H3, and DNA methylation could set up a heritable mark to establish a heterochromatin state of long-term silencing. b, pRb2/p130-coactivator complex regulate the ER-α transcription by maintaining a open chromatin conformation, in MCF-7 cells. The balance between HDAC1 and p300 activity permits high level of histone H3 and H4 acetylation; HDAC1 (histone deacetylase 1), SUV39H1 (histone methyl transferase), DNMTs (DNA methyl transferase), p300 (histone acetyl transferase), ICBP90 (methyl-CpG-binding and inverted CAAT-box-binding protein), TAFs (activator transcription factors), TFIIs (transcription factors.) (See further explanation in Macaluso et al, Cancer Research, 67(16): 7731-7, 2007

  EPIGENETIC AND GENETIC

BIOGRAPHY DETAILS

Marcella Macaluso, Ph.D.
Research Associate Professor
Director, Epigenetics & Genetics Program

tel: +1 215-204-9523
email: macaluso@temple.edu

Marcella Macaluso, Ph.D. is an Associate Professor of Biology and Director of the Epigenetic and  Genetic Program at S.H.R.O. Dr Macaluso’s research focuses on understanding the molecular mechanisms underlying epigenetic and genetic alterations in human cells leading to cancer formation and progression. Her interest is to investigate the complex network of signals by which pRb family proteins regulate cellular proliferation, survival and differentiation, and to disclose the mechanisms responsible for the regulatory disruption of these functions in the neoplastic process. Dr. Macaluso’s research has been supported by the Department of Defense Breast Cancer Research Program, by National Institute of Health (NIH), several private foundations and organizations. She can be reached at macaluso[at]temple.edu

Research Team:

Micaela Montanari, Research Assistant Professor
Valentina Caracciolo, Post-Doctoral Fellow
Francesco Paolo Fiorentino, PhD student

Daniel Burrit, Research Assistant

External Collaborators:

Christian Bronner, Ph.D.
Departement Pharmacologie et Physicochimie,
Faculte´ de Pharmacie, Institut Gilbert-Laustriat,
Centre National de la Recherche Scientifique, Illkirch, France

Mina Massaro-Giordano, M.D.
Scheie Eye Institute, University of Pennsylvania

Christine M. Marshall Research Specialist,
Department of Dermatology, University of Pennsylvania

Antonio Russo, M.D.
Dept. Oncology, University of Palermo, Palermo, Italy

Robert L. Copeland, Jr., Ph.D.
Department of Pharmacology,
College of Medicine
Howard University,
Washington, DC

  EPIGENETIC AND GENETIC

PUBLICATIONS

F Fiorentino , C Symonds , M Macaluso , A Giordano. Senescence and p130/pRb2: A New Beginning to the End. Cell Research, In press, 2009

M Macaluso, Micaela Montanari , Paul Bart Noto , Valter Gregorio, Christian Bronner and Antonio Giordano.Epigenetic modulation of Estrogen Receptor-alpha by pRb Family Proteins: A novel mechanism in breast cancer. Cancer Research 67(16):7731-7, 2007

M Achour, X Jacq, P Rondé, M Alhosin, C Charlot, T Chataigneau, M Jeanblanc, M Macaluso, A Giordano, AD Hughes, VB. Schini-Kerth, and C Bronner. The interaction of the SRA domain of ICBP90 with an unknown domain of DNMT1 is involved in the regulation of the VEGF gene expression. Oncogene, Oct 15, 2007

Caracciolo V, Reiss K, Crozier-Fitzgerald C, De Pascali F, Macaluso M , Khalili K, Giordano A. Interplay Between the Retinoblastoma Related pRb2/ p130 and E2F-4 and-5 in Relation to JCV-Tag. JCP, 212(1): 96-104, 2007

Gaetano Romano, Marcella Macaluso, Chiara Lucchetti and Lorraine Iacovitti Transcription and epigenetic profile of the promoter, first exon and first intron of the human tyrosine hydroxylase gene. JCP, 211(2): 431-8, 2007

Marcella Macaluso and Antonio Giordano. TMPRSS2: ERG gene fusion A new Genetic Marker for Prostate Cancer Progression. Cancer Biology & Therapy 6: 46-47, 2007

Macaluso M , Montanari M, Noto PB, Gregorio V, Surmacz E and Giordano A . Nuclear and cytoplasmic interaction of pRb2/p130 and ER- in MCF-7 breast cancer cells. Annals of Oncology, suppl 7: vii27-vii29, 2006

Montanari M, Macaluso M, Cittadini A and Giordano A. The role of geminin: from normal control of DNA replication to cancer formation and progression? Cell Death and Differentiation, 13(7): 1052-56, 2006

Macaluso M, Montanari M and Giordano A. Rb family proteins as modulators of gene expression and new aspects regarding the interaction with chromatin remodeling enzyme. Oncogene, 25(38): 5263-67, 2006

Macaluso M, Montanari M, Marshall CM , Gambone A, Tosi GM , Giordano A, and Massaro-Giordano M. Cytoplasmic and nuclear interaction between Rb family proteins and PAI-2: a physiological cross-talk in human cornea and conjunctiva cells. Cell Death and Differentiation, 13(9): 1515-22, 2006

C Augello, V Gregorio, V Bazan, P Cammareri, V Agnese, S Cascio, S Corsale,V Calò, A Gullo, R Passantino, G Gargano, L Bruno, G Rinaldi, V Morello, A Gerbino, RM Tomasino, M Macaluso, E Surmacz and A Russo. TP53 and p16INK4, but not H-Ki-Ras, are involved in tumorigenesis and progression of pleomorphic adenomas. JCP, 207(3):654-9, 2006

A Russo, S Corsale, V Agnese, M Macaluso, S Cascio, L Bruno, E Surmacz, G Dardanoni, MR Valerio, S Vieni, S Restivo, F Fulfaro, RM Tomasino , N Gebbia and V Bazan. TP53 mutations and s-phase fraction but not mutations in ras genes family and dna-ploidy are independent prognostic indicators in laryngeal squamous cell carcinoma. J Cell Physiol, 206(1):181-188, 2005

Cinti C, Macaluso M & Giordano A. Tumor-specific exon 1mutations could be the “hit event” predisposing Rb2/p130 gene to epigenetic silencing in lung cancer. Oncogene, 24(38):5821-5826, 2005

Macaluso M, Montanari M, and Giordano A. The regulation of ER-a transcription by pRb2/p130 in breast cancer.Annals of Oncology, 16 Suppl 4:iv20-iv22, 2005

G.M. Tosi, C. Trimarchi, M. Macaluso, D. La Sala, A. Ciccodicola, S. Lazzi, M. Massaro-Giordano, A. Caporossi, A. Giordano and C. Cinti. Genetic aand epigenetic alterations of pRb2/p130 tumor suppressor gene in human sporadic retinoblastoma: implications for pathogenesis and therapeutic approach. Oncogene,24(38):5827-5836, 2005

M Macaluso, M Montanari, C Cinti and A Giordano. Modulation of cell cycle components by epigenetic and genetic events. Seminars in Oncology, 32(5):452-457, 2005

N Normanno, A De Luca, MR. Maiello, Mancino, A D’Antonio, M Macaluso, F Caponigro and A  Giordano. Epidermal growth factor receptor (egfr) tyrosine kinaseinhibitors in breast cancer: current status and future development. Frontiers in Bioscience, Front Biosci, (10):2611-2617, 2005

A Russo, S Corsale, P Cammareri, V Agnese, G Di Fede, M Macaluso and

V Bazan. Pharmocogenomics in colorectal carcinoma: Future perspectives in personalized therapy. J Cell Physiol, 204(3):742-749, 2005

Bazan V, La Rocca G, Corsale S, Agnese V, Macaluso M, Migliavacca M, Gregorio V, Cascio S , Fiorentino E, Passantino R, Morello V, Gebbia N, Tomasino RM and Russo A. Laser pressure catapulting (lpc): optimization

lpc-system and genotyping of colorectal carcinomas. J Cell Physiol, 202 (2): 503-509, 2005

Giordano A and Macaluso M. Prognostic significance of pRb family and p16INK4 alterations in colorectal cancer: An interesting point of view in a complex net of molecular signals. Hum Pathol., 35(10):1171-2, 2004

Macaluso M and Giordano A. How does DNA methylation mark the fate of cells? Tumori, 90:367-372, 2004

Migliavacca M, Ottini L, Bazan V, Agnese V, Corsale S, Macaluso M, Lupi R, Dardanoni G, Valerio MR, Pantuso G, Di Fede G, Tomasino RM, Gebbia N, Mariani-Costantini R and Russo A. TP53 in gastric cancer: mutations in the L3 loop and LSH motif DNA-binding domains of TP53 predict poor outcome. J Cell Physiol, 200:476-85, 2004

Gan D-D, Macaluso M, Cinti C, Khalili K and Giordano A. How does a normal human cell become a cancer cell? J Exp Clin Cancer Res., 22(4):509-16, 2003

Macaluso M, Cinti C, Russo G, Russo A, Giordano A. pRb2/p130-E2F4/5-HDAC1-SUV39H1-DNMT1 multimolecular complexes mediate the transcription of Estrogen Receptor- in breast cancer. Oncogene, 22:3511- 7, 2003

Macaluso M, Paggi MG, Giordano A. Genetic and epigenetic alterations as hallmarks of the intricate road to cancer. Oncogene, 22:6472-8, 2003

La Sala D, Macaluso M, Trimarchi C, Giordano A, Cinti C. Triggering of p73-dependent apoptosis in osteosarcoma is under control of E2Fs-pRb2/p130 complexes Oncogene, 22:3518-29,2003

Calo V, Migliavacca M, Bazan V, Macaluso M, Buscemi M, Gebbia N, Russo A. STAT proteins: from normal control of cellular events to tumorigenesis. J Cell Physiol. ,197:157-68, 2003

Russo G, Claudio PP, Fu Y, Stiegler P, Yu Z, Macaluso M, Giordano A. pRB2/p130 target genes in non-small lung cancer cells identified by microarray analysis. Oncogene, 22:6959-69, 2003

Antonio Russo, Manuela Migliavacca, Ines Zanna, Marcella Macaluso, Nicola Gebbia, Viviana Bazan. Gatekeepers and Caretakers. Encyclopedia of the Human Genoma, 2003

L. De Martino, G. Marfé, C. Di Stefano, U. Pagnini, S. Florio, L. Crispino, G. Iovane , M. Macaluso and A. Giordano. Interference of Bovine herpesvirus 1 (BHV-1) in sorbitol-induced Apoptosis. J Cell Biochem., 89:373- 80, 2003

Bazan V, Zanna I, Migliavacca M, Sanz-Casla MT, Maestro ML, Corsale S, Macaluso M, Dardanoni G, Restivo S, Quintela PL, Bernaldez R, Salerno S, Morello V, Tomasino RM, Gebbia N, Russo A. Prognostic significance of p16INK4a alterations and 9p21 loss of heterozygosity in locally advanced laryngeal squamous cell carcinoma.J Cell Physiol., 192:286-93, 2002

V Bazan, M Migliavacca , C Tubiolo, M Macaluso, I Zanna, S Corsale, A

Amato, V Calò, G Dardanoni, V Morello, MLa Farina, I Albanese, R M

Tomasino, N Gebbia, and A Russo. Have P53 Gene Mutations And Protein Expression A Different Biological Significance In Colorectal Cancer? J Cell Physiol, 191:237-246, 2002

Macaluso M, Russo G, Cinti C, Bazan V, Gebbia N and Russo A. The Ras family genes: an interesting link between cell cycle and cancer. J Cell Physiol., 192:125-30, 2002

Pagnini U, Florio S, Crispino L, Pagnini G, Colangelo D, Rocco D, Pacilio C, Pacilio M, Macaluso M, Giordano A. “Direct effect of a gonadotropin-releasing hormone agonist on the growth of canine mammary tumour cells.” J Cell Biochem, 85:470-481, 2002

A. Russo, V. Bazan, M. Migliavacca, C. Tubiolo, M. Macaluso, I. Zanna, S. Corsale, F. Latteri, M.R. Valerio, G. Pantuso, V. Morello, G. Dardanoni, M.A. Latteri, G. Colucci, R.M. Tomasino N. Gebbia. DNA-aneuploidy and high proliferative activity but not Ki-ras2 mutations as indipendent predictors of clinical outocome in operable gastric carcinoma: results of a 5-years prospective study. Cancer, 92:294-302, 2001

Caterina Cinti and Marcella Macaluso, Risk of endometrial carcinoma associated with BRCA mutation. Gynecol Oncol, 80:395-8, 2001 (Critical Commentary)

M. Migliavacca, I. Zanna, C. Tubiolo, M. Macaluso, V. Bazan, A. Russo. Molecular Genetic of tumors: the cell cycle. Edizione Edises, 2001

I. Zanna, M. Migliavacca, C. Tubiolo, M. Macaluso ,V Bazan and A. Russo. Hereditary Tumors: molecular genetic and diagnosis. Edizioni Edises 2001

I.Zanna C.Tubiolo, M.Migliavacca, V.Bazan, M.Macaluso, S.Corsale, A. Amato, MA.Latteri, R.M.Tomasino, N.Gebbia, A.Russo. Hereditary breast cancer: Molecular genetics and clinical implications. 63rd course Advances in Oncology, Erice (Italy) 2001

Migliavacca, I. Zanna, V. Bazan, C. Tubiolo, M. Macaluso, S. Corsale, G. Dardanoni, N. Gebbia, R.M. Tomasino, M.A. Latteri, M. La Farina, I. Albanese, A. Russo. K-Ras and TP53 heterogenity in primary colorectal carcinomas and liver metastases: specific K-Ras mutations are associated with mucinous phenotype and clinical

outcome. The International Journal of Biological Markers, vol 15, 3: 279, 2000.

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