2004 Individual Investigator Award Recipient — Wael El Shamy, PhD

Project Summary

In some families, ovarian cancer is caused by the inaction of the tumor-suppressor gene, BRCA1. Dr. El Shamy has has discovered a second protein produced at the BRCA1 gene location, named IRIS, the function of which is not known. But Dr. El Shamy believes IRIS plays an opposite role in the life of ovarian cells, stimulating the growth and dispersion of these cells. Dr. El Shamy has found that IRIS over-expression in normal ovarian epithelial cells leads to dramatic down-regulation in the expression of the ovarian tumor suppressor, Disabled-2 (Dab-2), causing cancer growth and spread. In this project, Dr. El Shamy will investigate the role of IRIS in laboratory cells and in ovarian cancer tissue from women treated in the clinic to determine when IRIS is active, in which cancers IRIS is active, and the consequences of IRIS. IRIS may be a dangerous cancer-causing gene, and could be the target of future treatments of ovarian and breast cancers.

Bio

Associate Professor of Radiation Oncology and Pathlogy Director, Molecular Cancer Therapeutics Program PhD, Molecular Neurobiology, 1998, The Royal Karolinska for Medical Research, Stockholm, Sweden Postdoc, Cancer Biology, 1999-2002, Dana Farber Cancer Institute, Boston, MA, Instructor 2002-06, Medicine, Harvard Medical School, Boston, MA, Research interests

• Translational Research in breast and ovarian cancer
• Molecular biology study of BRCA1-IRIS and Geminin in breast and ovarian cancer metastases
• Development of drugs and/or drug regimens to target breast and ovarian cancer metastases

Research synopsis Recently, we discovered the novel oncogene, BRCA1-IRIS. Overexpression of BRCA1-IRIS in mammary or ovarian epithelial cells triggers aggressive traits, suggesting that BRCA1-IRIS is involved in the induction of metastasis in breast and ovarian cancer. The goal of our lab is to understand the cellular and molecular basis for BRCA1-IRIS' effects on mammary and ovarian epithelial cells, and to use this information to develop a BRCA1-IRIS-specific inhibitor for clinical use in preventing metastasis in cancer patients. We also rediscovered Geminin as an oncogene. Besides being an endogenous DNA-replication inhibitor, we found that Geminin is also involved in promoting cytokinesis and cell division when expressed at normal levels. In cancer cells, e.g. breast and ovarian cancer cells, Geminin overexpression causes cytokinesis to skip, resulting in tetraploid/aneuploid cells. Increasing amounts of evidence point to aneuploidy as a major cause of cancer metastasis. During the cell cycle, Geminin solubility oscillates, with soluble protein during S phase and insoluble protein in G2/M phase, in a phosphorylation-dependent manner. In G2/M, Geminin is bound to chromatin, centromeres and centrosomes and at the midbody during cytokinesis. When overexpressed, Geminin inhibits the function of several important mitotic-inducing proteins, such as Topoisomerase IIα and Aurora B kinase, leading to cytokinesis-skipping and the formation of tetraploid/aneuploid cells, and most likely metastatic cells in vivo. Our broader goals are to map these interactions on a molecular level, and use this information to find drugs or drug regimes that can inhibit Geminin or any of its interacting partners in cancer cells. Again, the ultimate goal is to find a drug to prevent the metastatic effects of Geminin in a clinical setting, saving patient lives. Recent accomplishments and honors 2010 - Session Chair, BIT 3rd Annual World Cancer Congress-2010; Health Science without borders 2009 - American Cancer Society scholar; Dr. Lawrence and Mrs. Bo Hing Chen Tsue American Cancer Society Scholar Selected publications

• BRCA1-IRIS inactivation overcomes paclitaxel resistance in triple negative breast cancers. Blanchard Z, Paul BT, Craft B, ElShamy WM. Breast Cancer Res. 2015 Jan 13;17(1):5.
• Geminin overexpression promotes imatinib sensitive breast cancer: a novel treatment approach for aggressive breast cancers, including a subset of triple negative. Blanchard Z, Mullins N, Ellipeddi P, Lage JM, McKinney S, El-Etriby R, Zhang X, Isokpehi R, Hernandez B, Elshamy WM. PLoS One. 2014 Apr 30;9(4):e95663.
• BRCA1-IRIS inactivation sensitizes ovarian cancer cells to Cisplatin, in vivo. Paul B, Blanchard Z, Ridgway M, ElShamy WM. Oncogene 2014, Aug. 2014
• Overview: Cellular plasticity, cancer stem cells and metastasis. ElShamy WM, Duhe RJ. Cancer Lett.2013 Nov 28; 341(1):2-8. doi: 10.1016/j.canlet.2013.06.020. Review.
• BRCA1-IRIS overexpression promotes formation of aggressive breast cancers. Shimizu Y, Luk H, Horio D, Miron P, Griswold M, Iglehart D, Hernandez B, Killeen J, ElShamy WM. PLoS One. 2012;7(4):e34102. doi: 10.1371/journal.pone.0034102. Epub 2012 Apr 12. PMID: 22511931