Breast Cancer Susceptibility Gene GT198 and Uses Thereof

a susceptibility gene and breast cancer technology, applied in the field of breast cancer susceptibility gene gt198, can solve the problems of insufficient explanation of specific risk factors for breast and ovarian cancer linked to hormone regulation, insufficient use of existing brca1 and brca2 genes for detecting breast and ovarian cancer and treating cancer,

Inactive Publication Date: 2010-10-21
MEDICAL COLLEGE OF GEORGIA RES INST +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Cancer is an often fatal disease that affects a significant portion of the population.
Breast cancer is the most common malignancy in women, and is a major cause of mortality in women over 45 years of age, especially in United States.
If the spread is not controlled, it can result in death.
However, the specific risk to breast and ovarian cancers that are evidently linked to hormone regulation has not been adequately explained.
Existing BRCA1 and BRCA2 genes for detecting breast and ovarian cancer and treating cancer are typically insufficient, especially for a large amount of sporadic cancers.

Method used

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  • Breast Cancer Susceptibility Gene GT198 and Uses Thereof
  • Breast Cancer Susceptibility Gene GT198 and Uses Thereof
  • Breast Cancer Susceptibility Gene GT198 and Uses Thereof

Examples

Experimental program
Comparison scheme
Effect test

example 1

Protein Sequence Homology Among GT198 and the BRC Repeats in BRCA2

[0115]GT198 has an N-terminal domain and a C-terminal DNA-binding domain (DBD) linked by a leucine zipper dimerization domain. Due to the functional similarities among GT198, BRCA1, and BRCA2 described below, we performed the multiple sequence alignment of BRCA1, BRCA2, and GT198 using ClustalW, and identified that the C-terminal DBD of GT198 is homologous to the BRC repeats in BRCA2 (FIG. 1). In particular, the C-terminal region of GT198 is aligned with the third and the fourth BRC repeats of BRCA2. The demonstrated Rad51-binding activity among these three sequences provides functional support for the presence of a potential BRC repeat in GT198. The N-terminus of GT198 showed limited homology to the BRC repeats. The functional implication of their sequence homology is that GT198 could compete with BRCA2 in binding to Rad51 through the BRC repeat region as illustrated in FIG. 1c.

example 2

GT198 is Co-Expressed with BRCA1 and BRCA2

[0116]The endogenous nuclear expression pattern of GT198 is remarkably similar to or almost indistinguishable from both BRCA1 and BRCA2 expression in mice (Chodosh, L. A., J Mammary Gland Biol Neoplasia, 3:389-402 (1998)). GT198 protein expression increases in primitive ectoderm at four days of embryoid bodies derived from embryonic stem cells. Consistent with the previous Northern blot analysis (Ko, L., et al., Mol Cell Biol, 22:357-69 (2002)), in situ hybridization revealed a marked increase in GT198 mRNA expression in neural tubes from E8.5 to E10.5 (data not shown). The expression peaks at E12.5 in all three germ layers and is downregulated at E18.5. In adult rodents, GT198 protein was predominantly found in testis with restricted expression in thymus, spleen and ovary by Western blot analysis (Ko, L., et al., Mol Cell Biol, 22:357-69 (2002)). Similar to BRCA1, GT198 mRNA expression can also be detected in different tissues. At the cellu...

example 3

Alternatively Spliced GT198 Variants Inhibit Wild Type GT198

[0117]During RT-PCR analysis of human GT198 mRNA expression, a number of GT198 alternative splice variants were identified. Alternative splicing of GT198 is tissue-specific with more variety of splicing variants were found in embryonic tissues or in cancer cells than in normal adult tissues. Sequencing results showed that all alternative splicing events occur strictly at the GT-AG consensus sites, some of which are supported by NCBI EST evidence. Interestingly, variations of alternative splicing always occurred at the 5′ half of the gene, and all generate premature stop codons with early termination of translation (FIG. 2a). All variant transcripts contain an open reading frame encoding the DBD (aa 126-217) with BRC repeat homology. A few variants also encode the N terminus. These truncated forms of potential proteins are devoid of the leucine zipper at amino acids 89-117 (Ko, L., et al., Mol Cell Biol, 22:357-69 (2002)), a...

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Abstract

It has been discovered that the human GT198 gene (gene symbol PSMC3IP) at chromosome 17q21 acts as a tumor suppressor. The mutation of the GT198 gene causes the increased dominant negative splice variant activity and leads to the loss of wild type GT198 function, and in turn, induces breast and ovarian cancers. One embodiment provides compositions and methods for treating or alleviating one or more symptoms associated with cancer due to the GT198 gene mutations. Another embodiment provides methods and compositions for detecting cancer due to the mutation of the GT198 gene. Still another embodiment provides methods for identifying compounds, antibodies and natural product molecules that are useful for treating cancer due to the mutations of the GT198 gene. Preferably the disclosed compositions antagonize or interfere with the biological activity of splice variants of GT198.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]This application claims priority to and benefit of U.S. Provisional Patent Application No. 61 / 212,974 filed on Apr. 20, 2009, and is incorporated herein by reference in its entirety.FIELD OF THE INVENTION[0002]Aspects of the invention are generally related to the field of molecular biology, gene diagnostics, and gene therapy.BACKGROUND OF THE INVENTION[0003]Cancer is an often fatal disease that affects a significant portion of the population. The National Cancer Institute estimated that the age-adjusted death rate due to cancer in the U.S. was 192.7 per 100,000 men and women per year. In January of 2003 approximately 10.5 million Americans had a history of cancer. Breast cancer is the most common malignancy in women, and is a major cause of mortality in women over 45 years of age, especially in United States. Each year over 185,000 new cases are diagnosed and more than 40,000 women die of the disease. However, only a very small percentage...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K39/395C12Q1/68A61K31/7088A61K31/7105A61P35/00
CPCC12Q1/6886C12Q2600/158C12Q2600/156C12Q2600/136A61P35/00A61K39/00A61K39/3955
Inventor KO, LAN
Owner MEDICAL COLLEGE OF GEORGIA RES INST
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