DF/HCC Program Affiliation

Kidney Cancer
Gastrointestinal Malignancies
Prostate Cancer
Cancer Immunology
Translational Pharmacology and Early Therapeutic Trials, Leader

DF/HCC Associations

Member, Center Scientific Council

Research Abstract

Basic research in the Kufe laboratory is focused on the role of the MUC1 protein in oncogenesis. Translational research efforts are directed toward the development of agents that target the MUC1 transforming function.

The Kufe laboratory identified the human DF3/MUC1 carcinoma-associated protein in the early 1980s. Initial studies demonstrated that MUC1 is aberrantly overexpressed in >90% of human breast cancers. Subsequent work by multiple laboratories showed that MUC1 is expressed at elevated levels by diverse carcinomas and certain hematologic malignancies. Estimates indicate that MUC1 is overexpressed in about 900,000 of the 1.4 million tumors diagnosed each year in the United States.

MUC1 is translated as a single polypeptide that undergoes autocleavage into two subunits that in turn form a stable heterodimer at the apical membrane of normal epithelial cells. The MUC1 N-terminal subunit (MUC1-N) contains tandem repeats that are rich in serine and threonine, and are subject to extensive O-glycosylation, a physical characteristic of mucin family members. MUC1-N is tethered to the apical cell membrane in a complex with the MUC1 C-terminal transmembrane subunit (MUC1-C).

Epithelia are single cell layers that separate multicellular animals from the external environment and are protected from adverse conditions by a mucous barrier. The secreted and transmembrane mucins that constitute the mucous barrier are of importance as a robust defense mechanism. Secreted mucins appeared early in metozoan evolution and evolved as more complex transmembrane structures that participate in the growth and survival of epithelia in vertebrates.

Early research on MUC1 focused on the shed MUC1-N mucin component and led to development of the CA15-3 assay to monitor circulating levels of this subunit as a tumor biomarker. Subsequent work then turned to the MUC1-C transmembrane subunit as the potential link between its overexpression and carcinogenesis. Indeed, the MUC1-C cytoplasmic domain was shown to be sufficient to induce transformation.

The MUC1-C subunit accumulates in the cytoplasm of transformed cells and is targeted to the nucleus and mitochondria. Moreover, the MUC1-C cytoplasmic domain directly contributes to the regulation of effectors, such as p53, β-catenin, NF-κB and STATs, that have been linked to transformation. The MUC1-C cytoplasmic domain also functions as a substrate for EGFR, MET, Src family members, c-Abl and GSK3β, supporting a role in diverse signaling pathways.

These findings have provided support for a model in which human tumors overexpress MUC1-C to exploit its role in promoting growth and survival. In addition, the overexpression in a substantial number of human malignancies has established it as a highly attractive target for the development of vaccines, antibodies and direct inhibitors.

Translational research in the Kufe laboratory has thus resulted in the development of a recombinant vaccinia virus expressing MUC1 that has completed Phase I trials and is under evaluation in Phase II studies for the treatment of MUC1-positive tumors. Another vaccine developed in the Kufe laboratory involves the fusion of MUC1-positive cancer cells with dendritic cells. Phase II trials of the fusion cell vaccine are underway in for patients with breast cancer, renal cancer, ovarian cancer and multiple myeloma.

Translational work is also underway to block MUC1-C subunit function with soluble receptors and antibodies against the MUC1-C extracellular domain. The demonstration that MUC1-C transforming function is dependent on the formation of oligomers has also provided the experimental framework for designing agents that block its oligomerization.

Publications

• Ahmad R, Raina D, Joshi MD, Kawano T, Ren J, Kharbanda S, Kufe D.MUC1-C oncoprotein functions as a direct activator of the nuclear factor-kappaB p65 transcription factor.Cancer Res 2009 Sep 1;69(17):7013-21.
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• Raina D, Ahmad R, Joshi MD, Yin L, Wu Z, Kawano T, Vasir B, Avigan D, Kharbanda S, Kufe D.Direct targeting of the mucin 1 oncoprotein blocks survival and tumorigenicity of human breast carcinoma cells.Cancer Res 2009 Jun 15;69(12):5133-41.
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• Pitroda SP,Khodarev NN,Beckett MA,Kufe DW,Weichselbaum RR.MUC1-induced alterations in a lipid metabolic gene network predict response of human breast cancers to tamoxifen treatment.Proc Natl Acad Sci U S A 2009 Apr 7;106(14):5837-41.
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• Kawano T, Ito M, Raina D, Wu Z, Rosenblatt J, Avigan D, Stone R, Kufe D.MUC1 oncoprotein regulates Bcr-Abl stability and pathogenesis in chronic myelogenous leukemia cells.Cancer Res 2007 Dec 15;67(24):11576-84.
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• Ahmad R, Raina D, Trivedi V, Ren J, Rajabi H, Kharbanda S, Kufe D.MUC1 oncoprotein activates the IkappaB kinase beta complex and constitutive NF-kappaB signalling.Nat Cell Biol 2007 Dec;9(12):1419-27.
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• Ramasamy S, Duraisamy S, Barbashov S, Kawano T, Kharbanda S, Kufe D.The MUC1 and galectin-3 oncoproteins function in a microRNA-dependent regulatory loop.Mol Cell 2007 Sep 21;27(6):992-1004.
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• Raina D, Ahmad R, Kumar S, Ren J, Yoshida K, Kharbanda S, Kufe D.MUC1 oncoprotein blocks nuclear targeting of c-Abl in the apoptotic response to DNA damage.EMBO J 2006 Aug 23;25(16):3774-83.
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• Wei X, Xu H, Kufe D.MUC1 oncoprotein stabilizes and activates estrogen receptor alpha.Mol Cell 2006 Jan 20;21(2):295-305.
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• Wei X, Xu H, Kufe D.Human MUC1 oncoprotein regulates p53-responsive gene transcription in the genotoxic stress response.Cancer Cell 2005 Feb;7(2):167-78.
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• Ren J, Agata N, Chen D, Li Y, Yu WH, Huang L, Raina D, Chen W, Kharbanda S, Kufe D.Human MUC1 carcinoma-associated protein confers resistance to genotoxic anticancer agents.Cancer Cell 2004 Feb;5(2):163-75.
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