Wael M. ElShamy, PhD
	Assistant Professor (Researcher), Cancer Research Center of Hawai‘i; Assistant Professor, Department of Pathology, John A. Burns School of Medicine, University of Hawai‘i PhD (Medicine) Royal Karolinska Institute, Stockholm, Sweden; MS (Molecular Biology), Stockholm University, Sweden; MS (Biochemistry), Stockholm University, Sweden welshamy@crch.hawaii.edu

Publication list via PubMed

Breast Cancer is a major affliction of women in western countries, with a lifetime risk of ~10% in the general population. Recent technological advances have resulted in earlier detection and better treatment. However, it is still the second leading cause of cancer death in women, exceeded only by lung cancer. Progression of breast cancer (i.e. invasion/metastases) is the major cause of these deaths. To help prevent breast cancer metastasis we must identify molecules and/or pathways that can be targeted with pharmacological inhibitors. In this regard we recently identified two molecules with increased ability to induce mammary epithelial cell motility, invasion and metastasis when overexpressed and the hope is to be able to prevent breast cancer metastasis by targeting them with pharmacological inhibitors.

The first molecule we named BRCA1-IRIS or IRIS (for In-frame Reading of BRCA1 Intron 11 Splice variant) was discovered as an alternate usage of the BRCA1 locus (). This discovery not only has the potential to explain the difference between the number of genes on the human genome (~30,000) and the number of functional proteins in the cell (~100,000), because it implies that any locus on the genome can be differentially used to generate 2 or more functionally different proteins. But this discovery also has the potential to lead to inhibition of metastasis. Because we found that IRIS when over-expressed can induce DNA over-replication, cellular over-proliferation and increased motility and invasive behavior. Thus one part of our research is devoted is dedicated to learning more about IRIS functions in order that in the near future we could find an inhibitor that can block IRIS expression and/or activity and help eradicate breast cancer progression and metastasis.

The second molecule, which we identified as an inducer of breast cancer metastasis was already known called Geminin. However, we discovered that unlike what was previously known about Geminin as a DNA replication inhibitor, which would suggest a tumor suppressor function, we found that Geminin in fact has an oncogenic function. We found that Geminin at the end of S phase is translocated from the soluble fraction of the nucleus in a phosphorylation-dependent manner to the insoluble fractions where it interacts with the cytokinetic machinery in M-phase and help induce proper anaphase and/or cyokinesis. When Geminin was selectively depleted, mammary cells failed to undergo cytokinesis. While its deliberate overexpression (which is seen in tumor cells) induced cytokinesis skipping and the production of tetraploid/aneuploid cells. It is this function that we wish to target with pharmacological inhibitor because we believe it is involved in the production of aggressive, invasive and drug resistant breast cancer cells that kill the patients. Thus, the other part of our research is dedicated to study this function in depth, isolate interacting partners of Geminin when it perform it and find that inhibitor that can prevent Geminin activity and breast cancer metastasis.

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Selected Publications

ElShamy WM, Livingston DM. Identification of BRCA1-IRIS, a BRCA1 locus product. Nat Cell Biol. 2004 Oct;6(10):954-67.

ElShamy WM, Livingston DM. Promoter usage of BRCA1-IRIS. Nat Cell Biol. 2005 Apr;7(4):326.

Nakuci E, Mahner S, Direnzo J, ElShamy WM. BRCA1-IRIS regulates cyclin D1 expression in breast cancer cells. Exp Cell Res. 2006 Oct 1;312(16):3120-31.

Hao L, ElShamy WM. BRCA1-IRIS activates cyclin D1 expression in breast cancer cells by downregulating the JNK phosphatase DUSP3/VHR.Int J Cancer. 2007 Jul 1;121(1):39-46.

Nakuci E, Xu M, Pujana MA, Valls J, ElShamy WM. Geminin is bound to chromatin in G2/M phase to promote proper cytokinesis. Int J Biochem Cell Biol. 2006;38(7):1207-20.

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