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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 evidences indicate that pRb-family proteins associate with a wide variety of transcription factors and chromatin remodelling 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, PhD. ia 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

u.Research Team:
Micaela Montanari, Post-Doctoral Fellow
Valentina Caracciolo, Post-Doctoral Fellow
Francesco Paolo Fiorentino, PhD student
Annalisa Roberti, PhD student

External Collaborators:
Christian Bronner, PhD
Departement Pharmacologie et Physicochimie,
Faculte´ de Pharmacie, Institut Gilbert-Laustriat,
Centre National de la Recherche Scientifique, Illkirch, France

Mina Massaro-Giordano, MD
Scheie Eye Institute, University of Pennsylvania

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

Antonio Russo, MD
Dept. Oncology, University of Palermo, Palermo, Italy

  EPIGENETIC AND GENETIC

PUBLICATIONS (2003-2006)

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

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

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

Cinti C, Macaluso M and 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

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

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

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

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):5263-5267, 2006.

Romano G, Macaluso M, Lucchetti C and Iacovitti L. Transcription and epigenetic profile of the promoter, first exon and first intron of the human tyrosine hydroxylase gene. J. Cell Physiol, 211(2):431-8, 2007

Macaluso M., Montanari M., Noto P.B., Gregorio V., Bronner C. and Giordano A. Epigenetic modulation of Estrogen Receptor-alpha by pRb Family Proteins: A novel mechanism in breast cancer. Cancer Res, 67(16):7731-7737, 2007

M Achour, X Jacq, P Rondé, M Alhosin, C Charlot, T Chataigneau, M Jeanblanc, M Macaluso, A Giordano, A D Hughes, V B Schini-Kerth and C Bronner. The interaction of the SRA domain of ICBP90 with a novel domain of DNMT1 is involved in the regulation of VEGF gene expression. Oncogene, advance online publication; doi: 10.1038/sj.onc.1210855, 2007

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