JAB1 as a prognostic marker and a therapeutic target for human cancer

Abstract

Methods of diagnosing and prognosticating the development of human cancers, such as breast cancer, colon cancer, and pancreatic cancer, are provided. The diagnostic and prognostic methods include the detection and / or quantifying of the amount of expression of JAB1 in human cells, particularly in relation to the amount of p27 or c-Jun. In addition, methods for reducing the expression of JAB1 protein in cells and inhibiting its interaction with p27 or c-Jun, for example, are provided.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This application claims priority to U.S. Provisional Patent Application 60 / 474,048 filed May 29, 2003, which is incorporated by reference herein in its entirety.STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT [0002] This invention was made with U.S. Government support from the National Cancer Institute / National Institutes of Health Grant number 1RO1CA90853-01A1. The U.S. Government may have certain rights in this invention.FIELD OF THE INVENTION [0003] The present invention relates generally to methods of diagnosing, prognosticating and treating human cancers, as well as assaying for therapeutic agents for treating human cancers. More specifically, the invention regards JUN activation binding protein 1 (JAB1)-associated embodiments for cancer diagnosis and therapy, such as breast cancer. BACKGROUND OF THE INVENTION [0004] Cancer can be caused by a wide variety of genetic abnormalities, such as hereditary or non-hereditar...

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Benefits of technology

[0019] As noted above, JAB1, aside from being an AP-1-coactivator, is involved in degradation of the cyclin-dependent kinase inhibitor p27. The present inventors examined JAB1 and p27 protein expression in the exemplary invasive breast carcinomas, colon cancer, and pancreatic cancer, for example, and identified the association of this expression with clinical outcome. JAB1 was detected immunohistochemically in the vast majority of tumors, with breast carcinomas showing high JAB1 expression and reduced or absent p27 levels. Tumors with high p27 expression were rarely positive for JAB1. Furthermore, all tested patients with JAB1-negative tumors had no evidence of relapse or disease progression at a median follow-up of 70 months. Immunoblotting showed strong JAB1 expression in breast carcinoma samples but not in paired normal breast epithelial samples, and JAB1 upregulation paralleled HER2 / neu overexpression. Targeted overexpression of JAB1 by regulated adenovirus in breast cancer cell lines also reduced p27 levels by accelerating its degradation. Thus, the JAB1 / p27 ratio is a novel indicator of aggressive, high-grade tumor behavior, and control of JAB1 provides a novel target for cancer therapy.

[0029] In additional aspects of the invention, blocking the interaction between JAB1 and p27 provides a mechanism for therapy of cancer. In particular embodiments, inhibiting this interaction facilitates arrest of cells and stops tumor growth. An agent to block the interaction may be of any kind, such as, for example, a polynucleotide, such as an RNA, a polypeptide, a peptide, a small molecule, and so forth. For example, the agent may be an inhibitor or ligand that binds to a pocket on JAB1 that is responsible at least in part for binding to its respective target, such as p27.

[0054] In a specific embodiment, an antisense agent is complementary to at least part of GenBank Accession No. NM—006837 (SEQ ID NO:9), for example, which can be obtained at the World Wide Web site of the National Center for Biotechnology Information. Other exemplary sequences include GenBank Accession Nos.: U65928 (SEQ ID NO:8); BC001859; (SEQ ID NO:14); BC007272 (SEQ ID NO:15); and BC001187 (SEQ ID NO:16). In a specific embodiment, the treating step is accomplished by delivering the antisense agent to the proliferating cells by direct transformation of the proliferating cells with the antisense agent, or microinjection, electroporation, or liposomal delivery of the antisense agent. The inhibition of expression of JAB1 in the proliferating cells may be accomplished by treating the cancer cells with an RNAi agent complementary to a JAB1 polynucleotide. In a specific embodiment, the RNAi agent is delivered directly to the proliferating cells. The RNAi agent may be chemically modified to increase a half-life and stability of the RNAi agent in the proliferating cells. The RNAi agent may be delivered to the proliferating cells by direct transformation of the proliferating cells with the RNAi agent, or by microinjection, electroporation, by catheter or liposomal delivery of the RNAi agent.

Problems solved by technology

However, overexpression of HER-2 protein via gene amplification of the HER-2 gene has been found to date in only approximately 25% of breast cancer patients.

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