Claudins as markers for early detection, diagnosis, prognosis and as targets of therapy for breast and metastatic brain or bone cancer

Abstract

Methods of diagnosis, prognosis, and treatment of breast cancer, and of metastatic brain cancer, are provided The diagnostic and prognostic methods involve the immunohistochemical detection of the level of expression of the proteins claudin 1, 3, 4, and 7 in tissue or cell samples. Claudins 1 and 7 are underexpressed in the majority of breast cancers, and claudins 3 and 4 are overexpressed. The methods of treatment involve the use of Clostridium perfringens enterotoxin (or a variant thereof) to lyse metastatic cancer cells in the brain and bone that overexpress claudins 3 and 4.

Description

[0001] This application claims priority to international patent application PCT / US03 / 04371, filed Feb. 14, 2003, which in turn claims priority to U.S. provisional patent application 60 / 356,860, filed Feb. 14, 2002 and 60 / 424,222, filed Nov. 6, 2002, the complete contents of which are hereby incorporated by reference.[0002] This invention was made using funds from grants from the Department of Defense having grant numbers DAMD17-01-0285 and DAMD17-02-1-0429. The United States government may have certain rights in this invention.BACKGROUND OF THE INVENTION [0003] 1. Field of the Invention [0004] The invention generally relates to the diagnosis, prognosis, and treatment of cancer. In particular, the invention provides the use of claudin proteins as targets for detection and treatment of primary epithelial cancers and metastatic brain and bone cancer. [0005] 2. Background of the Invention [0006] Breast cancer therapies have shown limited efficacy in patients with advanced disease making...

AI Technical Summary

Benefits of technology

[0099] A direct demonstration of the inverse correlation between CLDN-7 expression and cell-to-cell adhesion was sought by the treatment of breast cancer cell lines with hepatocyte growth factor/scatter factor (HGF/scatter factor). HGF is well known for its ability to decrease cell-to-cell adhesion and stimulate cell migration (Jiang et al., 1999). Breast cancer cell lines MCF-7 and T47D, which express high levels of CLDN-7 localized at the tight junction were treated with HGF/scatter factor for a period of 24 h. Western analysis was performed on equal amounts of total cell lysate using CLDN-7 and b-actin antibodies. The results showed a dramatic downregulation of CLDN-7 was observed in MCF-7, and to a lesser extent in T47D cells.

[0100] These data provide further direct evidence that loss of CLDN-7 occurs concurrently with loss of cell-to-cell adhesion.

[0101] To investigate the mechanism responsible for the loss of CLDN-7 expression, we first wanted to rule out the presence of mutations in the CLDN-7 mRNA (Accession #AJ011497) sequence. Nucleotide sequencing of the full-length cDNA revealed no mutations in the CLDN-7 coding sequences in all 11 primary IDCs tested (data not shown). Among the 11 tumors, six expressed very low or no CLDN-7 mRNA as determined by semiquantitative RT-PCR analysis.

[0102] The presence of CG-dinucleotide-rich sequences in the promoter region of genes is quite often a signature denoting that hypermethylation may be a potential mechanism for gene silencing (Ferguson et al., 2000; Evron et al., 2001a, b; Loeb et al., 2001; Jones and Baylin, 2002). The CLDN-7 promoter contains a CpG-rich region extending from −20 to −900 bp upstream of the translational start site (Accession #11425795). Therefore, we inves

Problems solved by technology

Breast cancer therapies have shown limited efficacy in patients with advanced disease making early diagnosis essential for long-term survival.

Further, few effective therapies for metastatic brain or bone cancer are currently available, and there is an ongoing need for promising therapy for these diseases as well.

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