WO2004008137A2 - Diagnosis and therapy of breast tumours resistant to antiestrogen treatment - Google Patents
Diagnosis and therapy of breast tumours resistant to antiestrogen treatment Download PDFInfo
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- WO2004008137A2 WO2004008137A2 PCT/EP2003/007449 EP0307449W WO2004008137A2 WO 2004008137 A2 WO2004008137 A2 WO 2004008137A2 EP 0307449 W EP0307449 W EP 0307449W WO 2004008137 A2 WO2004008137 A2 WO 2004008137A2
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/5005—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells
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- the invention is about a method to diagnose and therapy of breast tumours resistant to antiestrogen treatment by using specific target proteins and the nucleic acids encoding these proteins.
- the method is based on the determination of the differential expression of specific target proteins on the level of nucleic acids and proteins in antiestrogen-resistant breast tumour cells. Fields of application exist in medicine and the pharmaceutical industry.
- breast tumours are the most frequent type of cancer among women in the western industrialized countries.
- the hormone-dependent growth of mammary tumours is mediated primarily by a nuclear steroid hormone receptor — the estrogen receptor (ER).
- ER estrogen receptor
- prognosis and treatment strategies are determined on account of the estrogen receptor status.
- anti-hormone preparations are applied as an initial medication to these patients after surgical removal of the primary tumour.
- the anti-hormones are supposed to competitively displace the natural ligands (estrogen) from the receptor and thus inhibit the hormone- mediated growth of the tumours.
- Tamoxifen a non-steroidal antiestrogen
- the adjuvant application to prevent the development of metastasis is in the centre of attention (Harris 1992).
- tamoxifen therapy about one-third of the ER-positive tumours does not respond to tamoxifen therapy and a large number of patients develops resistance to the pharmaceutical drug in the course of treatment.
- Resistance to tamoxifen comprises a significant clinical problem to this day and its molecular cause is still unknown.
- the estrogen receptor itself is closely involved in the cellular transcription machinery. In the complex interaction with a large number of co-activator and co-repressor molecules it induces the expression of certain genes which, in turn, may be part of cellular signalling pathways.
- the objective of the invention consisted in finding new marker proteins which could serve as a therapeutic or diagnostic target when breast tumours show antiestrogen therapy resistance .
- the problem was solved by comparative investigations on a tamoxifen-sensitive mammary carcinoma xenograft (3366) and a tamoxifen-resistant sub- line (3366/TAM) created by a two-year treatment with tamoxifen (Naundorf et al., 2000). Proteins derived from tissue lysates of both tumour cell lines were examined by means of high-resolution two-dimensional (2D-) polyacrylamide gel-electrophoresis (examples are shown in Fig. 1).
- Proteins expressed at higher levels in the resistant cell line Proteins expressed at higher levels in the resistant cell line:
- Proteins expressed at lower levels in the resistant cell line • Glutamine hydrolysing GMP Synthase
- target proteins With the aid of these proteins (referred to as target proteins in the following) it is possible to assess tumour resistance to antiestrogen therapy.
- the objective of the invention is to create a method capable of assessing the resistance of breast tumour cells to antiestrogen therapy.
- the method is characterized by the fact that the concentration of at least one target protein is determined in the tumour tissue and is compared with the standard reference value of the same protein or proteins in breast tumour cells sensitive to antiestrogen treatment, whereat a separate standard reference value is determined once for each protein. If the protein concentration in the sample examined lies above the standard reference value, resistance of the tumour to antiestrogen treatment will be indicated, provided it is a protein which is expressed at higher levels in breast tumour cells resistant to antiestrogen treatment, as compared to breast tumour cells sensitive to antiestrogen treatment.
- the protein concentration in the sample examined lies below the standard reference value, resistance of the tumour to antiestrogen treatment will be indicated, provided it is a protein which is expressed at lower levels in breast tumour cells resistant to antiestrogen treatment, as compared to breast tumour cells sensitive to antiestrogen treatment.
- Deteraiination of the protein concentration is performed by applying known immunobiological methods, preferentially the application of antibodies, such as Western blot, immunohistochemistry, ELISA, among others.
- the invention comprises a test-kit to determine the concentrations of the target proteins in tumour samples.
- the invention also includes the therapeutic application of target proteins for the treatment of breast tumours that are resistant to antiestrogen treatment.
- nucleic acid sequences which are either identical or complementary to the cDNA sequences of the target proteins.
- these nucleic acid sequences can be applied as primers in a method to evaluate the resistance of breast tumour cells to antiestrogen treatment, by determining the concentrations of nucleic acids encoding specific target proteins in the tumour tissue and comparing them with a standard reference value of the same nucleic acids in the breast tumour tissues that are sensitive to antiestrogen treatment, whereat a separate standard reference value is determined once for each nucleic acid fragment.
- the concentration of the nucleic acid fragment in the sample examined lies above the standard reference value, resistance of the tumour to antiestrogen treatment will be indicated, provided it is a nucleic acid segment which is expressed at a higher level in breast tumour cells resistant to antiestrogen treatment, as compared to breast tumour cells sensitive to antiestrogen treatment. If the concentration of the nucleic acid segment in the sample examined lies below the standard reference value, resistance of the tumour to antiestrogen treatment will be indicated, provided it is a nucleic acid segment which is expressed at lower levels in breast tumour cells resistant to antiestrogen treatment, as compared to breast tumour cells sensitive to antiestrogen treatment.
- the invention includes the application of nucleic acid segments which are either identical with or complementary to the cDNA sequences of the target proteins, for example, in the in form of antisense oligonucleotides for the treatment of breast tumours resistant to antiestrogen therapy.
- the invention includes the blocking of the synthesis of the target proteins on the level of RNA, preferentially by means of antisense oligonucleotides or ribozyme directed against the mRNA encoding these proteins.
- This blocking is also possible, according to the invention, by means of specific antibodies directed against these proteins.
- Fig. 1 Examples of comparative 2D gel electrophoresis
- the images show the differential expression of selected proteins in three samples of tamoxifen-sensitive (above) and tamoxifen-resistant cell lines (below).
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Abstract
The invention is about a method to diagnose and therapy breast tumors resistant to antiestrogen treatment by using specific target proteins and the nucleic acids encoding these proteins. The method is based on the determination of the differential expression of specific target genes on the nucleic acids and protein level in antiestrogen-resistant breast tumor cells. Fields of application exist in medicine and in the pharmaceutical industry. The method is characterized by the fact, that the concentration of at least one specific target protein is determined in tumor tissue and is compared with the standard reference value of the same protein or proteins in breast tumor tissue sensitive to antiestrogen treatment, whereat a protein concentration of the sample examined lying above the standard reference value indicates tumor resistance to antiestrogen treatment, provided it is a protein which is expressed at a higher level in breast tumor cells resistant to antiestrogen treatment, as compared to breast tumor cells sensitive to antiestrogen treatment, or a protein concentration of the sample examined lying below the standard reference value indicates tumor resistance to antiestrogen treatment, provided it is a protein which is expressed at a lower level in breast tumor cells resistant to antiestrogen treatment, as compared to breast tumor cells sensitive to antiestrogen treatment.
Description
Method to Diagnose and Therapy of Breast Tumours Resistant to
Antiestrogen Treatment
Description
The invention is about a method to diagnose and therapy of breast tumours resistant to antiestrogen treatment by using specific target proteins and the nucleic acids encoding these proteins. The method is based on the determination of the differential expression of specific target proteins on the level of nucleic acids and proteins in antiestrogen-resistant breast tumour cells. Fields of application exist in medicine and the pharmaceutical industry.
Breast tumours are the most frequent type of cancer among women in the western industrialized countries. The hormone-dependent growth of mammary tumours is mediated primarily by a nuclear steroid hormone receptor — the estrogen receptor (ER). As of today, prognosis and treatment strategies are determined on account of the estrogen receptor status. As approximately two-thirds of the tumours are found to dispose this receptor, anti-hormone preparations are applied as an initial medication to these patients after surgical removal of the primary tumour. The anti-hormones are supposed to competitively displace the natural ligands (estrogen) from the receptor and thus inhibit the hormone- mediated growth of the tumours.
Tamoxifen, a non-steroidal antiestrogen, is most frequently applied to treat mammary carcinomas, whereat the adjuvant application to prevent the development of metastasis is in the centre of attention (Harris 1992). Unfortunately, about one-third of the ER-positive tumours does not respond to tamoxifen therapy and a large number of patients develops resistance to the pharmaceutical drug in the course of treatment. Resistance to tamoxifen comprises a significant clinical problem to this day and its molecular cause is still unknown.
As a ligand-inducible transcription factor the estrogen receptor itself is closely involved in the cellular transcription machinery. In the complex interaction with a large number of
co-activator and co-repressor molecules it induces the expression of certain genes which, in turn, may be part of cellular signalling pathways.
The fact that nearly 15% of the ER-negative primary tumours also respond to tamoxifen, is an indication to the existence of other ER-independent cellular antiestrogen binding sites. Therefore, resistance to tamoxifen is apparently due to more complex molecular mechanisms which are based on an impaired balance of transcription cofactors, growth factors, signal transduction pathways, or oncogenes (Clarke et al. 2001). Concerning the optimisation of hormone therapy of breast tumours, it would be desirable to predict tumour responses prior to the respective anti-hormone therapy, in order to avoid an unnecessary therapy whose cancerogenous potential has been repeatedly subject of discussion.
The objective of the invention consisted in finding new marker proteins which could serve as a therapeutic or diagnostic target when breast tumours show antiestrogen therapy resistance .
The problem was solved by comparative investigations on a tamoxifen-sensitive mammary carcinoma xenograft (3366) and a tamoxifen-resistant sub- line (3366/TAM) created by a two-year treatment with tamoxifen (Naundorf et al., 2000). Proteins derived from tissue lysates of both tumour cell lines were examined by means of high-resolution two-dimensional (2D-) polyacrylamide gel-electrophoresis (examples are shown in Fig. 1).
Comparative gel evaluations were carried out with the aid of appropriate computer programs, in order to trace differentially expressed proteins, this means, proteins expressed to various degrees. Interesting protein spots displaying significant differences were punched out and in gel-digested with trypsin. Resulting mixtures of peptides were analysed by MALDI mass-spectrometry.
Surprisingly, we thus succeeded to identify several proteins that are clearly, i.e. more than two-fold, under- or overexpressed in tamoxifen-resistant tumours, as compared to tamoxifen-sensitive tumours.
The following proteins have been identified as marker proteins for antiestrogen therapy resistance of breast tumours:
Proteins expressed at higher levels in the resistant cell line:
• Peroxiredoxin 1
SwissProt*: Acc-No. Q06830 Locus: PDX1_HUMAN
• Vinculin (Metavinculin) SwissProt*: Acc.-No. P18206 Locus: NINC_HUMAN
• Lysophospholipase I, Acyl-Protein Thioesterase 1 NCBI-REFSEQ*: Acc-No. NM_006330.2 Locus: P_006321
• C8ORF2-Protein, Chromosome 8 "open reading frame" 2
NCBI-REFSEQ*: Acc-No. NM_007175.2 Locus: NP_009106
• Peroxiredoxin 4, Thioredoxin Peroxidase
SwissProt Acc-No. Q13162 Locus:PDX4_HUMAN
• Voltage-Dependent, Anion-Selective Channel Protein 1, outer mitochondrial membrane protein Porin 1
SwissProt Acc-No. P21796 Locus PORl_HUMAN
• 40S Ribosomal Protein, Laminin Receptor
SwissProt Acc-No. P08865 Locus RSP4_HUMAN
• Endothelial actin-binding Protein
SwissProt Acc-No. P21333 Locus FLNA_HUMAN
• Ubiqumol-Cytochrome C Reductase Iron-Sulphur Subunit SwissProt Acc-No. P47985 Locus UCRI_HUMAN
Proteins expressed at lower levels in the resistant cell line: • Glutamine hydrolysing GMP Synthase
SwissProt*: Acc-No. P49915 Locus: GUAA_HUMAN
• DJ-1 Protein
NCBI*: Acc-No. BAA09603 Locus: HUMDJl RNA-Binding Protein (Regulatory Subunit)
NCBI*: Acc-No. CAB52550 Locus: CAB52550
(both proteins are identical)
• 27 kDa Heat Shock Protein (HSP27) SwissProt*: Acc-No. P04792 Locus: HS27_HUMAN
• ALG-2 Interacting Protein, programmed cell death 6 interacting protein NCBI Acc-No. NP_037506 Locus PDCD6IP
• Cyclophilin A, peptidyl-propyl cis-trans isomerase
SwissProt Acc-No. P05092 Locus CYPH_HUMAN
• 60S Acidic Ribosomal Protein P0
SwissProt Acc-No. P05388 Locus RLA0 HUMAN
With the aid of these proteins (referred to as target proteins in the following) it is possible to assess tumour resistance to antiestrogen therapy.
The invention is realised in accordance with the Claims stated.
The objective of the invention is to create a method capable of assessing the resistance of breast tumour cells to antiestrogen therapy. The method is characterized by the fact that the concentration of at least one target protein is determined in the tumour tissue and is compared with the standard reference value of the same protein or proteins in breast tumour cells sensitive to antiestrogen treatment, whereat a separate standard reference value is determined once for each protein. If the protein concentration in the sample examined lies above the standard reference value, resistance of the tumour to antiestrogen treatment will be indicated, provided it is a protein which is expressed at higher levels in breast tumour cells resistant to antiestrogen treatment, as compared to breast tumour cells sensitive to antiestrogen treatment. If the protein concentration in the sample examined lies below the standard reference value, resistance of the tumour to antiestrogen treatment will be indicated, provided it is a protein which is expressed at lower levels in breast tumour cells resistant to antiestrogen treatment, as compared to breast tumour cells sensitive to antiestrogen treatment.
Deteraiination of the protein concentration is performed by applying known immunobiological methods, preferentially the application of antibodies, such as Western blot, immunohistochemistry, ELISA, among others. Moreover, the invention comprises a test-kit to determine the concentrations of the target proteins in tumour samples.
The invention also includes the therapeutic application of target proteins for the treatment of breast tumours that are resistant to antiestrogen treatment.
Subject of the invention are also nucleic acid sequences which are either identical or complementary to the cDNA sequences of the target proteins. Experience shows that these nucleic acid sequences can be applied as primers in a method to evaluate the resistance of breast tumour cells to antiestrogen treatment, by determining the concentrations of nucleic acids encoding specific target proteins in the tumour tissue and comparing them with a standard reference value of the same nucleic acids in the breast tumour tissues that are sensitive to antiestrogen treatment, whereat a separate standard reference value is determined once for each nucleic acid fragment.
If the concentration of the nucleic acid fragment in the sample examined lies above the standard reference value, resistance of the tumour to antiestrogen treatment will be indicated, provided it is a nucleic acid segment which is expressed at a higher level in breast tumour cells resistant to antiestrogen treatment, as compared to breast tumour cells sensitive to antiestrogen treatment. If the concentration of the nucleic acid segment in the sample examined lies below the standard reference value, resistance of the tumour to antiestrogen treatment will be indicated, provided it is a nucleic acid segment which is expressed at lower levels in breast tumour cells resistant to antiestrogen treatment, as compared to breast tumour cells sensitive to antiestrogen treatment. In addition, the invention includes the application of nucleic acid segments which are either identical with or complementary to the cDNA sequences of the target proteins, for example, in the in form of antisense oligonucleotides for the treatment of breast tumours resistant to antiestrogen therapy.
Furthermore, the invention includes the blocking of the synthesis of the target proteins on the level of RNA, preferentially by means of antisense oligonucleotides or ribozyme directed against the mRNA encoding these proteins. This blocking is also possible, according to the invention, by means of specific antibodies directed against these proteins.
Legend of Figure:
Fig. 1: Examples of comparative 2D gel electrophoresis
The images show the differential expression of selected proteins in three samples of tamoxifen-sensitive (above) and tamoxifen-resistant cell lines (below). a) Spot 857 - Lysophospholipase I Spot 866 - Peroxiredoxin I b) C80RF2-Protein (hypothetical 37.8-kDa-Protein, function unknown) c) Ubiquinol - Cytochrome c reductase
Literature:
Harris JR, Lippman ME, Veronesi U, Willett W: Breast cancer. New England J Med 327:319-328 (1992)
Clarke R, Leonessa F, Welch JM, Skaar TC: Cellular and molecular pharmacology of antiestrogen action and resistance. Pharm Rev 53:25-71 (2001)
Naundorf H, Becker M, Lykkesfeldt AE, Elbe B, Neumann C, Buttner B, Fichtner I: Development and characterization of a tamoxifen-resistant breast carcinoma xenograft. Br. J. Cancer 82:1844 (2000)
Claims
1. Method to evaluate the resistance of breast tumour cells to antiestrogen therapy, wherein
a) the concentration of at least one specific target protein is determined in tumour tissue; and
b) is compared with the standard reference value of the same protein or proteins in breast tumour tissue sensitive to antiestrogen treatment,
whereat a protein concentration in the sample examined which lies above the standard reference value indicates a resistance of the tumour to antiestrogen treatment, if it is a protein that is expressed at a higher level in breast tumour cells resistant to antiestrogen treatment, as compared to breast tumour cells sensitive to antiestrogen treatment, or,
a protein concentration in the sample examined which lies below the standard reference value indicates a resistance of the tumour to antiestrogen treatment, if it is a protein that is expressed at a lower level in breast tumour cells resistant to antiestrogen treatment, as compared to breast tumour cells sensitive to antiestrogen treatment.
2. Method in accordance with Claim 1 , wherein the following proteins: • Peroxiredoxin 1
SwissProt*: Acc-No. Q06830 Locus: PDX1_HUMAN
• Vinculin (Metavinculin) SwissProt*: Acc-No. P18206 Locus: VINC HUMAN
• Lysophospholipase I, Acyl-Protein Thioesterase 1 NCBI-REFSEQ*: Acc-No. NM_006330.2 Locus: NP_006321
• C8ORF2-Protein, Chromosome 8 "open reading frame" 2 NCBI-REFSEQ*: Acc-No. NM_007175.2 Locus: NP_009106
• Glutamine-hydrolysing GMP Synthase SwissProt* : Acc-No. P49915 Locus: GUAA HUMAN
• DJ-1 Protein NCBI*: Acc-No. BAA09603 Locus: HUMDJ1
• RNA-Binding Protein (Regulatory Subunit)
NCBI*: Acc-No. CAB52550 Locus: CAB52550
(both proteins are identical)
• 27 kDa Heat Shock Protein (HSP27) SwissProt*: Acc-No. P04792 Locus: HS27 HUMAN
• Peroxiredoxin 4, Thioredoxin Peroxidase SwissProt Acc-No. Q13162 Locus:PDX4 HUMAN
Voltage-Dependent, Anion-Selective Channel Protein 1, outer mitochondrial membrane protein Porin 1
SwissProt Acc-No. P21796 Locus POR1 HUMAN
40S Ribosomal Protein, Laminin Receptor
SwissProt Acc-No. P08865 Locus RSP4 HUMAN
• Endothelial Actin-Binding Protein SwissProt Acc-No. P21333 Locus FLNA HUMAN
Ubiquinol-Cytochrome c reductase Iron-Sulphur subunit
SwissProt Acc-No. P47985 Locus UCRI HUMAN
ALG-2 interacting protein, programmed cell death 6 interacting protein NCBI Acc-No. NP 037506 Locus PDCD6IP
Cyclophilin A, Peptidyl-propyl cis-trans isomerase
SwissProt Acc-No. P05092 Locus CYPH HUMAN • 60S Acidic Ribosomal Protein P0
SwissProt Acc-No. P05388 Locus RLA0 HUMAN
are applied as the target proteins.
3. Method in accordance with the Claims 1 und 2, wherein at least one of the following target proteins:
• Peroxiredoxin 1
SwissProt*: Acc-No. Q06830 Locus: PDXI TUMAN
• Vinculin (Metavinculin)
SwissProt*: Acc-No. P18206 Locus: VTNC HUMAN
• Lysophospholipase I, Acyl-Protein Thioesterase 1 NCBI-REFSEQ*: Acc-No. NM_006330.2 Locus: NP_006321
• C8ORF2-Protein, Chromosome 8 "open reading frame" 2 NCBI-REFSEQ*: Acc-No. NM_007175.2 Locus: NP_009106
• Peroxiredoxin 4, Thioredoxin Peroxidase
SwissProt Acc-No. Q13162 Locus:PDX4_HUMAN
• Voltage-Dependant, Anion-Selective Channel Protein 1, outer mitochondrial membrane protein Porin 1 SwissProt Acc-No. P21796 Locus PORIJHUMAN
• 40S Ribosomal Protein, Laminin Receptor
SwissProt Acc-No. P08865 Locus RSP4_HUMAN
• Endothelial Actin-Binding Protein
SwissProt Acc-No. P21333 Locus FLNA_HUMAN
• Ubiquinol-Cytochrome c Reductase Iron-Sulphur Subunit
SwissProt Acc-No. P47985 Locus UCRI_HUMAN is expressed at a higher level in breast tumour cells resistant to antiestrogen freatment, as compared to breast tumour cells sensitive to antiesfrogen freatment.
4. Method in accordance with Claim 3, wherein the concentration of at least one of the target proteins is at least twice as high in breast tumour cells resistant to antiestrogen freatment, as compared to breast tumour cells sensitive to antiestrogen treatment.
5. Method in accordance with Claims 1 to 2, wherein the concenfration of at least one of the following target proteins:
• Glutamine-hydrolysing GMP Synthase
SwissProt*: Acc-No. P49915 Locus: GUAA ΪUMAN
• DJ-1 Protein NCBI*: Acc-No. BAA09603 Locus: HUMDJ1
RNA-Binding Protein (Regulatory Subunit)
NCBI*: Acc-No. CAB52550 Locus: CAB52550
(both proteins are identical)
• 27 kDa Heat Shock Protein (HSP27)
SwissProt*: Acc-No. P04792 Locus: HS27 HUMAN
• ALG-2 Interacting Protein, programmed cell death 6 interacting protein NCBI Acc-No. NP_037506 Locus PDCD6LP
• Cyclophilin A, Peptidyl-Propyl cis-frans Isomerase
SwissProt Acc-No. P05092 Locus CYPH_HUMAN
• 60S Acidic Ribosomal Protein P0
SwissProt Acc-No. P05388 Locus RLA0_HUMAN
is lower in breast tumour cells resistant to antiestrogen freatment, as compared to breast tumour cells sensitive to antiesfrogen treatment.
6. Method in accordance with Claim 5, wherein the concenfration of at least one target protein is twofold lower in breast tumour cells resistant to antiesfrogen treatment than in breast tumour cells sensitive to antiesfrogen freatment.
7. Method in accordance with Claims 1 to 6, wherein the determination of the protein concentrations is performed by applying immunological methods.
8. Method in accordance with Claim 7, wherein the determination of the protein concentrations is performed by applying antibodies which are directed against the target proteins.
9. Method in accordance with Claim 8, wherein the determination of the protein concentrations is performed by applying the Western blot technique, immunohistochemistry, the ELISA technique or other methods of protein determination.
10. Method to evaluate the resistance of breast tumour cells to antiestrogen treatment, wherein a) the concentration of at least one nucleic acid segment which encodes a particular target protein is determined in the tumour cells; and
b) is compared with the standard reference value of the same nucleic acid segment or segments in breast tumour cells sensitive to antiestrogen treatment, whereat a concentration of the nucleic acid segment in the sample examined that lies above the standard reference value indicates a tumour resistance to antiestrogen therapy, provided it is a segment that is expressed at a higher level in breast tumour cells resistant to antiestrogen treatment than in breast tumour cells sensitive to antiesfrogen treatment, and a concentration of the nucleic acid segment in the sample examined that lies below the standard reference value indicates a tumour resistance to antiestrogen treatment, provided it is a segment that is expressed at a lower level in breast tumour cells resistant to antiesfrogen treatment than in breast tumour cells sensitive to antiestrogen treatment.
11. Method in accordance with Claim 10, wherein the concenfration of the nucleic acid segments is determined by PCR or other suitable methods.
12. Use of the method in accordance with Claims 1 to 11 to diagnose resistance to the treatment of breast tumours with tamoxifen.
13. Use of the method in accordance with Claims 1 to 11 for the freatment of breast tumours resistant to antihormonal freatment.
14. Use in accordance with Claim 13, wherein an increase of the concentration of the following proteins:
• Peroxiredoxin 1
SwissProt*: Acc-No. Q06830 Locus: PDX1_HUMAN
• Vinculin (Metavinculin)
SwissProt*: Acc-No. P18206 Locus: VLNC_HUMAN
• Lysophospholipase I, Acyl-Protein Thioesterase 1
NCBI-REFSEQ*: Acc-No. NM_006330.2 Locus: NP_006321
• C8ORF2-Protein, Chromosome 8 "open reading frame" 2
NCBI-REFSEQ*: Acc-No. NM_007175.2 Locus: NP_009106
• Peroxiredoxin 4, Thioredoxin Peroxidase SwissProt Acc-No. Q13162 Locus:PDX4_HUMAN
• Voltage-Dependent, Anion-Selective Channel Protein 1 , outer mitochondrial membrane protein Porin 1
SwissProt Acc-No. P21796 Locus PORl_HUMAN
• 40S Ribosomal Protein, Laminin-Receptor
SwissProt Acc-No. P08865 Locus RSP4_HUMAN
• Endothelial Actin-binding Protein SwissProt Acc-No. P21333 Locus FLNA HUMAN • Ubiquinol-Cytochrome C Reductase Iron-Sulphur Subunit
SwissProt Acc-No. P47985 Locus UCRI_HUMAN
in the tumour cells is prevented, or an increased concentration is eliminated, and antihormonal freatment is either initiated or continued.
15. Use in accordance with Claim 14, wherein the increased concenfration of the proteins is prevented by blocking protein synthesis on the level of RNA, preferentially by means of antisense oligonucleotides or ribozyme directed against the mRNA encoding these proteins.
16. Use in accordance with Claim 14, wherein the function of higher expressed target proteins is blocked or hampered by means of specific antibodies directed against these proteins.
17. Use in accordance with Claim 13, wherein an increased concenfration of the proteins:
• Glutamine-hydrolysing GMP Synthase
SwissProt*: Acc-No. P49915 Locus: GUAA_HUMAN
• DJ-1 Protein
NCBI*: Acc-No. BAA09603 Locus: HUMDJ1
RNA-Binding Protein (Regulatory Subunit) NCBI*: Acc-No. CAB52550 Locus: CAB52550
(both proteins are identical)
• 27 kDa Heat Shock Protein (HSP27)
SwissProt*: Acc-No. P04792 Locus: HS27_HUMAN
• ALG-2 Interacting Protein, programmed cell death 6 interacting protein NCBI Acc-No. NP B7506 Locus PDCD6IP
• Cyclophilin A, Peptidyl-Propyl cis-frans Isomerase SwissProt Acc-No. P05092 Locus CYPH HUMAN • 60S Acidic Ribosomal Protein P0
SwissProt Acc-No. P05388 Locus RLA0_HUMAN
in the tumour cells is generated and antiesfrogen freatment is either initiated or continued.
18. Use in accordance with the Claims 14 to 17, wherein antiestrogenic therapeutics, preferentially tamoxifen, are applied.
19. Test-kit to determine antiestrogen freatment resistance of breast tumours, wherein it contains one or several antibodies directed against at least one of the following proteins:
• Peroxiredoxin 1
SwissProt*: Acc-No. Q06830 Locus: PDX1JHUMAN
• Vinculin (Metavinculin)
SwissProt*: Acc-No. P18206 Locus: VINC_HUMAN
• Lysophospholipase I, Acyl-Protein Thioesterase 1 NCBI-REFSEQ*: Acc-No. NM_006330.2 Locus: NP_006321
• C8ORF2-Protein, Chromosome 8 "open reading frame" 2 NCBI-REFSEQ*: Acc-No. NM_007175.2 Locus: NP_009106
• Glutamine-hydrolysing GMP Synthase
SwissProt*: Acc-No. P49915 Locus: GUAA_F1UMAN
• DJ-1 Protein
NCBI*: Acc-No. BAA09603 Locus: HUMDJl
RNA-Binding Protein (Regulatory Subunit)
NCBI*: Acc-No. CAB52550 Locus: CAB52550
(both proteins are identical)
• 27 kDa Heat Shock Protein (HSP27) SwissProt*: Acc-No. P04792 Locus: HS27 HUMAN
• Peroxiredoxin 4, Thioredoxin Peroxidase
SwissProt Acc-No. Q13162 Locus:PDX4_HUMAN
• Voltage-Dependant, Anion-Selective Channel Protein 1, outer mitochondrial membrane protein Porin 1
SwissProt Acc-No. P21796 Locus PORl_HUMAN
• 40S Ribosomal Protein, Laminin-Receptor
SwissProt Acc-No. P08865 Locus RSP4_HUMAN
• Endothelial Actin-Binding Protein
SwissProt Acc-No. P21333 Locus FLNA_HUMAN
• Ubiquinol-Cytochrome C Reductase Iron-Sulphur Subunit SwissProt Acc-No. P47985 Locus UCRI_HUMAN
• ALG-2 Interacting Protein, programmed cell death 6 interacting protein NCBI Acc-No. NP_037506 Locus PDCD6IP
• Cyclophilin A, Peptidyl-Propyl cis-trans Isomerase
SwissProt Acc-No. P05092 Locus CYPH_HUMAN
• 60S Acidic Ribosomal Protein P0
SwissProt Acc-No. P05388 Locus RLA0_HUMAN
20. Test-kit to determine antiestrogen treatment resistance of breast tumours, wherein it contains one or several primer pairs capable to amplify at least one of the nucleic acid sequences of the mRNA encoding the following proteins:
• Peroxiredoxin 1
SwissProt*: Acc-No. Q06830 Locus: PDX1_HUMAN
• Vinculin (Metavinculin) SwissProt*: Acc-No. P18206 Locus: VP C HUMAN • Lysophospholipase I, Acyl-Protein Thioesterase 1 NCBI-REFSEQ*: Acc-No. NM_006330.2 Locus: NP_006321
• C8ORF2-Protein, Chromosome 8 "open reading frame" 2 NCBI-REFSEQ*: Acc-No. NM_007175.2 Locus: NP_009106
• Glutarnine-hydrolysing GMP Synthase SwissProt*: Acc-No. P49915 Locus: GUAA HUMAN
• DJ-1 Protem NCBI*: Acc-No. BAA09603 Locus: HUMDJ1
RNA-Binding Protein (Regulatory Subunit) NCBI*: Acc-No. CAB52550 Locus: CAB52550
(both proteins are identical)
• 27 kDa Heat Shock Protein (HSP27) SwissProt*: Acc-No. P04792 Locus: HS27 HUMAN
• Peroxiredoxin 4, Thioredoxin Peroxidase SwissProt Acc-No. Q 13162 Locus:PDX4 HUMAN
• Voltage-Dependent, Anion-Selective Channel Protein 1, outer mitochondrial membrane protein Porin 1 SwissProt Acc-No. P21796 Locus POR1 HUMAN
• 40S Ribosomal Protein, Laminin Receptor
SwissProt Acc-No. P08865 Locus RSP4 HUMAN
Endothelial Actin-Binding-Protein SwissProt Acc-No. P21333 Locus FLNA HUMAN
• Ubiquinol-Cytochrome C Reductase Iron-Sulphur Subunit SwissProt Acc-No. P47985 Locus UCRIJHUMAN
• ALG-2 Interacting Protein, programmed cell death 6 interacting protein NCBI Acc-No. NP 037506 Locus PDCD6IP • Cyclophilin A, Peptidyl-Propyl cis-frans Isomerase
SwissProt Acc-No. P05092 Locus CYPH TUMAN
• 60S Acidic Ribosomal Protein P0 SwissProt Acc-No. P05388 Locus RLAO ΪUMAN
*Swissprot and NCBI Protein Database (www.ncbi.nlm.nih.gov/Entrez)
Swiss-Prot EMBL-Outstation - European Bioinformatics Institute Hinxton, Cambridge CB10 1SD, UK
NCBI
National Center for Biotechnology Information National Library of Medicine Bethesda, MD, USA
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| AU2003253050A AU2003253050A1 (en) | 2002-07-12 | 2003-07-10 | Diagnosis and therapy of breast tumours resistant to antiestrogen treatment |
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE10231873.5 | 2002-07-12 | ||
| DE10231873 | 2002-07-12 | ||
| DE10310198.5 | 2003-03-06 | ||
| DE10310198A DE10310198A1 (en) | 2002-07-12 | 2003-03-06 | Methods for the diagnosis and therapy of anti-estrogen therapy-resistant breast tumors |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| WO2004008137A2 true WO2004008137A2 (en) | 2004-01-22 |
| WO2004008137A3 WO2004008137A3 (en) | 2004-09-02 |
Family
ID=30116640
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/EP2003/007449 Ceased WO2004008137A2 (en) | 2002-07-12 | 2003-07-10 | Diagnosis and therapy of breast tumours resistant to antiestrogen treatment |
Country Status (2)
| Country | Link |
|---|---|
| AU (1) | AU2003253050A1 (en) |
| WO (1) | WO2004008137A2 (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005123944A1 (en) * | 2004-06-18 | 2005-12-29 | Roche Diagnostics Gmbh | Use of protein pdx1 as a marker for breast cancer |
| WO2012100600A1 (en) * | 2011-01-24 | 2012-08-02 | 中国人民解放军第三军医大学 | Use of specific antibodies for peroxiredoxin iv in preparing in vitro diagnostic reagents for early-stage rheumatoid arthritis |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU2001238700A1 (en) * | 2000-02-22 | 2001-09-03 | Board Of Regents, The University Of Texas System | Compositions and methods of use of het, a novel modulator of estrogen action |
-
2003
- 2003-07-10 WO PCT/EP2003/007449 patent/WO2004008137A2/en not_active Ceased
- 2003-07-10 AU AU2003253050A patent/AU2003253050A1/en not_active Abandoned
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005123944A1 (en) * | 2004-06-18 | 2005-12-29 | Roche Diagnostics Gmbh | Use of protein pdx1 as a marker for breast cancer |
| WO2012100600A1 (en) * | 2011-01-24 | 2012-08-02 | 中国人民解放军第三军医大学 | Use of specific antibodies for peroxiredoxin iv in preparing in vitro diagnostic reagents for early-stage rheumatoid arthritis |
Also Published As
| Publication number | Publication date |
|---|---|
| WO2004008137A3 (en) | 2004-09-02 |
| AU2003253050A8 (en) | 2004-02-02 |
| AU2003253050A1 (en) | 2004-02-02 |
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