Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving antigen-antibody binding – specific binding protein...
Reexamination Certificate
1999-05-06
2002-11-19
Ungar, Susan (Department: 1642)
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving antigen-antibody binding, specific binding protein...
C435S007920, C435S007930, C435S007940, C435S007950, C435S960000, C435S962000, C530S387100, C530S350000
Reexamination Certificate
active
06482600
ABSTRACT:
GOVERNMENT RIGHTS
Not applicable.
FIELD OF THE INVENTION
This invention relates to the discovery of the association of certain nucleic acid sequences and proteins with breast cancer. The identification of these breast cancer-associated nucleic acid sequences and proteins have diagnostic uses in detecting the breast cancer status of a cell population as well as application for therapy of breast cancer.
BACKGROUND OF THE INVENTION
Breast cancer is a major affliction of women in developed countries. It is estimated in the United States, for example, that 12 percent of all women will be given a diagnosis of breast cancer and 3.5 percent will die of the disease. The incidence rates of the disease increase as women enter their fourth decade of life such that breast cancer is the leading cause of death for women aged 40-55. Though incidence of the disease is high, early diagnosis is key for the long-term survival of a patient afflicted with the disease. Additional methods which will aid in the early diagnosis of the disease and provide a better understanding of it are sorely needed.
SUMMARY OF THE INVENTION
This invention provides for isolated nucleic acid sequences and proteins whose overexpression is associated with breast cancer. Overexpression of any of the subject proteins is indicative of the disease. Methods and materials for detection of such overexpression are described. The invention has application to primary and advanced or metastatic breast cancer. The invention also embraces the use of screening assays for identifying useful pharmaceutical agents, antisense methods for studying breast cancer in animals and cells and therapeutic methods for inhibiting the growth of breast cancer tumor cells.
DEFINITIONS
“Amplification” primers are oligonucleotides comprising either natural or analog nucleotides that can serve as the basis for the amplification of a select nucleic acid sequence. They include both polymerase chain reaction primers and ligase chain reaction oligonucleotides.
“Antibody” refers to a polypeptide substantially encoded by an immunoglobulin gene or immunoglobulin genes, or fragments thereof which specifically bind and recognize an analyte (antigen). The recognized immunoglobulin genes include the kappa, lambda, alpha, gamma, delta, epsilon and mu constant region genes, as well as the myriad immunoglobulin variable region genes. Light chains are classified as either kappa or lambda. Heavy chains are classified as gamma, mu, alpha, delta, or epsilon, which in turn define the immunoglobulin classes, IgG, IgM, IgA, IgD and IgE, respectively.
An exemplary immunoglobulin (antibody) structural unit comprises a tetramer. Each tetramer is composed of two identical pairs of polypeptide chains, each pair having one “light” (about 25 kD) and one “heavy” chain (about 50-70 kD). The N-terminus of each chain defines a variable region of about 100 to 110 or more amino acids primarily responsible for antigen recognition. The terms variable light chain (V
L
) and variable heavy chain (V
H
) refer to these light and heavy chains respectively.
Antibodies exist e.g., as intact immunoglobulins or as a number of well characterized fragments produced by digestion with various peptidases. Thus, for example, pepsin digests an antibody below the disulfide linkages in the hinge region to produce F(ab)′
2
, a dimer of Fab which itself is a light chain joined to V
H
-C
H
1 by a disulfide bond. The F(ab)′
2
may be reduced under mild conditions to break the disulfide linkage in the hinge region, thereby converting the F(ab)′
2
dimer into an Fab′ monomer. The Fab′ monomer is essentially an Fab with part of the hinge region (see,
Fundamental Immunology
, Third Edition, W. E. Paul, ed., Raven Press, N.Y. 1993). While various antibody fragments are defined in terms of the digestion of an intact antibody, one of skill will appreciate that such fragments may be synthesized de novo either chemically or by utilizing recombinant DNA methodology. Thus, the term antibody, as used herein, also includes antibody fragments either produced by the modification of whole antibodies or those synthesized de novo using recombinant DNA methodologies (e.g., single chain Fv).
“Associated” in the context of breast cancer refers to a relationship of the relevant nucleic acid sequences and their overexpression of the subject protein in a cell as an indicator that the cell is a breast cancer cell.
“Biological samples” refers to any tissue or liquid sample having genomic DNA or other nucleic acids (e.g., mRNA) or proteins. It includes both cells with a normal complement of chromosomes and cells suspected of breast cancer.
The term “gene” means the segment of DNA involved in producing a polypeptide chain; it includes regions preceding and following the coding region (leader and trailer) as well as intervening sequences (introns) between individual coding segments (exons).
The term “isolated”, when applied to a nucleic acid or protein, denotes that the nucleic acid or protein is essentially free of other cellular components with which it is associated in the natural state. It is preferably in a homogeneous state although it can be in either a dry or aqueous solution. Purity and homogeneity are typically determined using analytical chemistry techniques such as polyacrylamide gel electrophoresis or high performance liquid chromatography. A protein which is the predominant species present in a preparation is substantially purified. In particular, an isolated gene is separated from open reading frames which flank the gene and encode a protein other than the gene of interest. The term “purified” denotes that a nucleic acid or protein gives rise to essentially one band in an electrophoretic gel. Particularly, it means that the nucleic acid or protein is at least 85% pure, more preferably at least 95% pure, and most preferably at least 99% pure.
The term “nucleic acid” refers to deoxyribonucleotides or ribonucleotides and polymers thereof in either single- or double-stranded form. Unless specifically limited, the term encompasses nucleic acids containing known analogues of natural nucleotides which have similar binding properties as the reference nucleic acid and are metabolized in a manner similar to naturally occurring nucleotides. Unless otherwise indicated, a particular nucleic acid sequence also implicitly encompasses conservatively modified variants thereof (e.g. degenerate codon substitutions) and complementary sequences and as well as the sequence explicitly indicated. Specifically, degenerate codon substitutions may be achieved by generating sequences in which the third position of one or more selected (or all) codons is substituted with mixed-base and/or deoxyinosine residues (Batzer et al.,
Nucleic Acid Res
. 19:5081 (1991); Ohtsuka et al.,
J. Biol Chem
. 260:2605-2608 (1985); and Cassol et al., 1992; Rossolini et al.,
Mol. Cell. Probes
8:91-98 (1994)). The term nucleic acid is used interchangeably with gene, cDNA, and mRNA encoded by a gene.
“Nucleic acid derived from a gene” refers to a nucleic acid for whose synthesis the gene, or a subsequence thereof, has ultimately served as a template. Thus, an mRNA, a cDNA reverse transcribed from an mRNA, an RNA transcribed from that cDNA, a DNA amplified from the cDNA, an RNA transcribed from the amplified DNA, etc., are all derived from the gene and detection of such derived products is indicative of the presence and/or abundance of the original gene and/or gene transcript in a sample.
As used herein a “nucleic acid probe” is defined as a nucleic acid capable of binding to a target nucleic acid (e.g., a nucleic acid associated with breast cancer) of complementary sequence through one or more types of chemical bonds, usually through complementary base pairing, usually through hydrogen bond formation. As used herein, a probe may include natural (i.e. A, G, C, or T) or modified bases (7-deazaguanosine, inosine, etc.). In addition, the bases in a probe may be joined by a linkage other than a phosphodiester bond, so long as it does not interfer
Brown Joseph P.
Burmer Glenna C.
Ford Amanda A.
Davis Minh Tam
LifeSpan BioSciences, Inc.
Ungar Susan
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