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.
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.
Epigenetic regulation of ER-α by pRb2/p130 in breast cancer
Hypothetical model of how pRb2/p130-complexes may regulate ER-α transcription
Marcella Macaluso, Ph.D.
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
Daniel Burrit, Research Assistant
Christian Bronner, Ph.D.
Robert L. Copeland, Jr., Ph.D.
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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