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1. (WO2008008284) CANCER BIOMARKERS AND METHODS OF USE THREOF
注意: このテキストは、OCR 処理によってテキスト化されたものです。法的な用途には PDF 版をご利用ください。

CLAIMS

What is claimed is:

1. An array of a plurality of distinct binding agents displayed on a surface of a solid support, wherein each of said binding agents comprises at least a specific epitope binding domain of an antibody that specifically binds a target protein that is differentially expressed in a pre-cancerous epithelial cell, wherein said target protein is selected from COX-2, Ki67, pi 6, CD73, CD 138, notch receptor-3, CD90, BMM, IGF2, YKL-40, EGF-R, c-jun, PCNA, jnk, cyclin Bl , c-kit, STAT3, cyclin Dl, PI3K, MAPK, MAPKK, DDR2, TRF2, activin, and MEK1/2.

2. The array of claim 1 , wherein said target protein is selected from COX-2, Ki67, and pl6.

3. The array of claim 1 , wherein said target protein is selected from CD73, CDl 38, notch receptor-3, CD90, BMI-I, and cyclooxygenase-2.

4. The array of claim 1, wherein the array comprises a binding agent that specifically binds CD73 and a binding agent that specifically binds CD90.

5. A set of distinct protein-binding agents, wherein each of said protein-binding agents comprises at least a specific epitope binding domain of an antibody that specifically binds a target protein that is differentially expressed in a pre-cancerous epithelial cell, wherein said target protein is selected from CD73, CDl 38, notch receptor-3, CD90, BMI-I, COX-2, Ki67, pi 6, IGF2, YKL-40, EGF-R, c-jun, PCNA, jnk, cyclin Bl, c-kit, STAT3, cyclin Dl, PI3K, MAPK, MAPKK, DDR2, TRF2, activin, and MEK1/2.

6. The set of claim 5, wherein each of said protein-binding agents comprises a detectable label.

7. The set of claim 6, wherein the detectable label is selected from gold, a fluorescent protein, a chromogenic protein, a fluorescent dye, an enzyme, and biotin.

8. The set of claim 7, wherein the fluorescent protein is a green fluorescent protein, a red fluorescent protein, a yellow fluorescent protein, or a blue fluorescent protein.

9. The set of claim 5, wherein said target protein is a cell surface protein.

10. A method of detecting a pre-cancerous mammary epithelial cell in a sample, the method comprising detecting one or more target proteins that are differentially expressed in a precancerous epithelial cell.

1 1. The method of claim 10, wherein the one or more target proteins are selected from CD73, CD138, notch receptor-3, CD90, BMI-I, COX-2, Ki67, pl6, IGF2, YKL-40, EGF-R, c-jun, PCNA, jnk, cyclin Bl, c-kit, STAT3, cyclin Dl, PI3K, MAPK, MAPKK, DDR2, TRF2, activin, TRF2, activin, and MEK1/2.

12. The method of claim 10, wherein the one or more target proteins is selected from COX-2, Ki67, and pl6.

13. The method of claim 10, wherein the one or more target proteins are selected from CD73, CDl 38, notch receptor-3, CD90, BMI-I, and cyclooxygenase-2.

14. The method of claim 10, wherein the one or more target proteins are CD73 and CD90.

15. A method of determining the risk that a pre-cancerous mammary epithelial cell will become cancerous, the method comprising detecting one or more targeted proteins that are differentially expressed in a pre-cancerous epithelial cell.

16. The method of claim 15, wherein the one or more target proteins are selected from CD73, CD138, notch receptor-3, CD90, BMI-I, COX-2, Ki67, pl6, IGF2, YKL-40, EGF-R, c-jun, PCNA5 jnk, cyclin Bl, c-kit, STAT3, cyclin Dl, PI3K, MAPK, MAPKK, DDR2, TRF2, activin, and

MEK1/2.

17. The method of claim 15, wherein the one or more target proteins are selected from COX-2, Ki67, and pl6.

18. The method of claim 15, wherein the one or more target proteins are selected from CD73, CDl 38, notch receptor-3, CD90, BMI-I, and cyclooxygenase-2.

19. The method of claim 15, wherein the one or more target proteins are CD73 and CD90.

20. A method of imaging a pre-cancerous mammary epithelial cell in an individual, the method comprising administering to the individual a detectably labeled antibody reagent that binds specifically to a target protein that is differentially expressed in a pre-cancerous mammary epithelial cell; and detecting binding of the antibody reagent to a pre-cancerous mammary epithelial cell in the individual.

21. A method of determining the risk that an individual will develop a malignant cancer, the method comprising detecting the level in a mammary epithelial cell obtained from the individual of a target polypeptide that is differentially expressed in a pre-cancerous mammary epithelial cell.

22. The method of claim 21, wherein the individual has been diagnosed with low-grade ductal carcinoma in situ.

23. The method of claim 21 , wherein the individual has been diagnosed with high-grade ductal carcinoma in situ.

24. The method of claim 21 , wherein the individual has been diagnosed as having a benign breast biopsy.

25. The method of claim 21 , wherein the individual has been previously determined to be at high risk of developing a malignant cancer.

26. A method of detecting a pre-cancerous epithelial cell in an individual, the method comprising detecting a methylation status of a p 16 promoter in the genome of an epithelial cell in a sample obtained from the individual, wherein the methylation status provides an indication of a precancerous state of the epithelial cell.

27. An isolated, immortalized variant human mammary epithelial cell (vHMEC), wherein the vHMEC is CD73+, and wherein the vHMEC is genetically modified to comprise a nucleic acid comprising a nucleotide sequence encoding an oncogene.

28. The isolated, immortalized vHMEC of claim 27, wherein the oncogene is v-Ha-ras.

29. The isolated, immortalized vHMEC of claim 28, wherein the nucleotide sequence encoding the oncogene is operably linked to a constitutive promoter.

30. The isolated, immortalized vHMEC of claim 27, wherein the vHMEC is further genetically modified with a nucleic acid comprising a nucleotide sequence encoding a protein that provides a detectable signal.

31. A method of detecting an effect of a component of stroma on tumor progression in a human mammary epithelial cell (HMEC), the method comprising:
a) contacting a test stomal component in vitro with an immortalized variant HMEC
(vHMEC) according to claim 27; and
b) determining the effect, if any, of the test stromal component on a cell characteristic of the immortalized vHMEC,
wherein a test stromal component that induces a cell characteristic change in the immortalized vHMEC that is indicative of tumor progression indicates that the test stromal component has potential to induce tumor progression in an HMEC.

32. The method of claim 31 , wherein the test stromal component is a fibroblast.

33. The method of claim 31 , wherein the cell characteristic is a morphological change.

34. The method of claim 31 , wherein the cell characteristic is acquisition of a mesenchymal feature.

35. The method of claim 31, wherein the cell characteristic is increased motility.

36. A method of isolating a variant human mammary epithelial cell (vHMEC) from a mixed cell population comprising a vHMEC, the method comprising:
a) contacting a mixed cell population comprising a vHMEC with an antibody specific for CD73, wherein the antibody binds to CD73 present on the surface of the vHMEC, forming a complex between the anti-CD73 antibody and the vMEC; and
b) separating the complex from the sample.

37. An array of a plurality of distinct nucleic acid binding agents displayed on a surface of a solid support, wherein each of said nucleic acid binding agents comprises a nucleotide sequence that specifically binds a target mRNA that is differentially expressed in a pre-cancerous epithelial cell, wherein said target mRNA is selected from CD73, CDl 38, notch receptor-3, CD90, BMI-I, COX-2, Ki67, ρl6, IGF2, YKL-40, EGF-R, c-jun, PCNA, jnk, cyclin Bl, c-kit, STAT3, cyclin Dl, PI3K, MAPK, MAPKK, DDR2, TRF2, activin, and MEK1/2.

38. A method of imaging a pre-cancerous mammary epithelial cell in an individual, the method comprising:
detecting in the individual a pre-cancerous mammary epithelial cell that has been labeled with an agent that provides for selective labeling of a cell that exhibits altered metabolism.

39. The method of claim 38, wherein said detecting comprises magnetic resonance imaging, positron emission tomography, or magnetic resonance imaging.