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Epigenetic Modulation of Estrogen Receptor- by pRb Family Proteins: A Novel Mechanism in Breast Cancer

¹ Sbarro Institute for Cancer Research and Molecular Medicine, Center of Biotechnology, College of Science and Technology, Temple University, Philadelphia, Pennsylvania; ² Department of Human Pathology and Oncology, University of Siena, Siena, Italy; ³ Section of Oncology, Department of Oncology, University of Palermo, Palermo, Italy; and ⁴ Département Pharmacologie et Physicochimie, Faculté de Pharmacie, Institut Gilbert-Laustriat, UMR 7175-LC1 Centre National de la Recherche Scientifique/Université Louis Pasteur (Strasbourg I), Illkirch, France

Requests for reprints: Marcella Macaluso, Sbarro Institute for Cancer Research and Molecular Medicine, Center of Biotechnology, College of Science and Technology, Temple University, Philadelphia, PA 19122. Phone: 215-204-9523; Fax: 215-204-9522; E-mail: macaluso{at}temple.edu or Antonio Giordano, Sbarro Institute for Cancer Research and Molecular Medicine, Center of Biotechnology, College of Science and Technology, Temple University, Philadelphia, PA 19122. Phone: 215-204-9520; Fax: 215-204-9522; E-mail: Giordano{at}temple.edu.

Estrogen receptor- (ER-) plays a crucial role in normal breast development and has also been linked to mammary carcinogenesis and clinical outcome in breast cancer patients. However, ER- gene expression can change during the course of disease and, consequently, therapy resistance can occur. The molecular mechanism governing ER- transcriptional activity and/or silencing is still unclear. Here, we showed that the presence of a specific pRb2/p130 multimolecular complex on the ER- promoter strongly correlates with the methylation status of this gene. Furthermore, we suggested that pRb2/p130 could cooperate with ICBP90 (inverted CCAAT box binding protein of 90 kDa) and DNA methyltransferases in maintaining a specific methylation pattern of ER- gene. The sequence of epigenetic events for establishing and maintaining the silenced state of ER- gene can be locus- or pathway- specific, and the local remodeling of ER- chromatin structure by pRb2/p130 multimolecular complexes may influence its susceptibility to specific DNA methylation. Our novel hypothesis could provide a basis for understanding how the complex pattern of ER- methylation and transcriptional silencing is generated and for understanding the relationship between this pattern and its function during the neoplastic process. [Cancer Res 2007;67(16):7731–7]