WO2009033293A1 - Protéine tyrosine phosphatase 1b et cancer - Google Patents

Protéine tyrosine phosphatase 1b et cancer Download PDF

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WO2009033293A1
WO2009033293A1 PCT/CA2008/001627 CA2008001627W WO2009033293A1 WO 2009033293 A1 WO2009033293 A1 WO 2009033293A1 CA 2008001627 W CA2008001627 W CA 2008001627W WO 2009033293 A1 WO2009033293 A1 WO 2009033293A1
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ptp1
cancer
ndl2
tumor
ptp1b
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PCT/CA2008/001627
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Michel L. Tremblay
Sophie G. Julien
Nadia DUBÉ
Willian J. Muller
Anne-Marie Mes-Masson
Fred Saad
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The Royal Institution For The Advancement Of Learning/Mcgill University
Centre De Recherche Chum
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
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    • C12Q1/6886—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material for cancer
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    • 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
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/574—Immunoassay; Biospecific binding assay; Materials therefor for cancer
    • G01N33/57484—Immunoassay; Biospecific binding assay; Materials therefor for cancer involving compounds serving as markers for tumor, cancer, neoplasia, e.g. cellular determinants, receptors, heat shock/stress proteins, A-protein, oligosaccharides, metabolites
    • G01N33/57496—Immunoassay; Biospecific binding assay; Materials therefor for cancer involving compounds serving as markers for tumor, cancer, neoplasia, e.g. cellular determinants, receptors, heat shock/stress proteins, A-protein, oligosaccharides, metabolites involving intracellular compounds
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    • C12Q2600/00—Oligonucleotides characterized by their use
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    • C12Q2600/136—Screening for pharmacological compounds
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    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/158—Expression markers

Definitions

  • the present invention relates to the identification of a marker gene useful in the diagnosis and prognosis of cancer, e.g. breast cancer and prostate cancer.
  • the invention further provides methods for determining the course of treatment of a patient with cancer.
  • the present invention relates to methods of screening for anti-cancer therapeutics and methods of cancer diagnosis and prognosis using protein tyrosine phosphatase 1 B (PTP1 B) as a marker.
  • PTP1 B protein tyrosine phosphatase 1 B
  • Oncogenic activation of ErbB2 can either be triggered by point mutations in its transmembrane domain 4 ' 5 or by deletion or insertion in the extracellular domain (ECD) 4 ' 6 ' 7 .
  • ECD extracellular domain
  • transgenic mice were generated that overexpressed in mammary gland, an altered neu transgene containing an in-frame deletion in its ECD (NDL2) 6 .
  • NDL2 females develop multiple mammary tumors with frequent lung metastasis lesions. Tumor progression in this strain is associated with elevated levels of tyrosine-phosphorylated ErbB2 and ErbB3 7 which have also been shown to be co-expressed in the majority of human breast cancers 8 ' 9 .
  • Prostate cancer is a leading cause of male cancer-related death, second only to lung cancer, and is estimated to afflict one out of nine men over the age of 65. In the United States alone, well over 40,000 men die annually of this disease. Despite the magnitude of these figures, there is still no effective treatment for metastatic prostate cancer. Surgical prostatectomy, radiation therapy, hormone ablation therapy, and chemotherapy remain as the main treatment options. Unfortunately, these treatments are ineffective for many and are often associated with significant undesirable consequences. [0006] Prostate cancer is typically diagnosed with a digital rectal exam, prostate specific antigen (PSA) screening and/or trans-rectal ultrasound.
  • PSA prostate specific antigen
  • PSA is used as a marker for prostate cancer because it is secreted only by prostate cells and an elevated serum PSA level can indicate the presence of prostate cancer.
  • PSA screening has been a useful diagnostic tool, the specificity, sensitivity and general utility of PSA is widely regarded as lacking in several respects. Neither PSA testing, nor any other test nor biological marker has been proven capable of reliably identifying early-stage disease. Similarly, there is no marker available for predicting the emergence of the typically fatal metastatic stage of the disease. There is a need for improved diagnostic and therapeutic methods to improve the detection, prognosis, treatment and management of the disease.
  • PTP1 B function in order to acquire new means to influence cell and body metabolism for the treatment and prevention of human diseases, particularly cancer.
  • the present invention relates to the identification of PTP1 B as a genetic marker whose expression is correlated with cancer, for example breast cancer or prostate cancer.
  • the invention provides a marker whose expression can be used to select a subject who will respond to or benefit from treatment with a PTP1 B inhibitor.
  • the invention relates to methods of using this marker to select subjects for treatment with a PTP1 B inhibitor.
  • a subject with high or elevated levels of PTP1B expression is administered a PTP1 B inhibitor in a therapeutically effective amount.
  • PTP1 B levels are a marker for treatment with PTP1 B inhibitors. Diagnostic methods and kits for measuring PTP1B levels and selecting patients for treatment with PTP1 B inhibitors are provided herein.
  • a diagnostic method for identifying subjects who will respond to or benefit from treatment with a PTP1 B inhibitor comprising measuring PTP1 B levels during and after treatment with a PTP1 B inhibitor and comparing to PTP1 B levels measured before treatment commences.
  • PTP1 B levels may decrease in patients responding to treatment with a PTP1 B inhibitor.
  • kits for diagnosing a cancer in a subject comprising one or more than one reagent for detecting PTP1 B expression or measuring PTP1 B levels, and instructions for use of said one or more than one reagent, wherein elevated levels of PTP1 B are diagnostic of cancer or of a predisposition to cancer.
  • the methods and kits of the invention may also be used for determining prognosis of a patient.
  • kits for assigning treatment to a patient comprising one or more than one reagent for detecting PTP1 B expression or measuring PTP1 B levels, and instructions for use of said one or more than one reagent, wherein a patient with elevated levels of PTP1 B is assigned treatment with one or more PTP1 B inhibitors.
  • PTP1 B may be detected using standard methods such as PCR, antibodies, immunocytochemistry, immunoprecipitation, DNA probes, aptamers, small molecules, etc. Small molecules may be tagged with a detectable agent or labelled for imaging purposes.
  • PTP1 B levels are measured in a tumor of a subject having ErbB2 positive cancer to select the subject for treatment with PTP1 B inhibitors.
  • kits for assigning treatment to a patient having a cancer comprising reagents for detecting PTP1 B expression or measuring PTP1B levels, and instructions for use of said reagents, wherein a patient with elevated levels of PTP1 B is assigned treatment with one or more PTP1 B inhibitors.
  • the patient may for example have a cancer which expresses PTP1 B and one or more known oncogenic proteins, such as EGFRvIII, EGFR/HER-1/ErbB1, ErbB2/HER-2, ErbB3/HER-3, ErbB4/HER-4, ras, myc, BRCA1 , and BRCA2.
  • the invention further provides for methods of assigning therapeutic regimen to cancer patients, e.g. breast or prostate cancer patients.
  • the invention provides a method of assigning a therapeutic regimen to a cancer patient, comprising measuring PTP1 B levels in said patient, wherein said therapeutic regimen assigned to said patient comprises PTP1B inhibitor therapy if said PTP1B levels are high.
  • said patient has breast cancer, e.g. ErbB2 positive cancer.
  • said patient has prostate cancer.
  • said patient is assigned PTP1 B inhibitor therapy in combination with a first anti-cancer therapy.
  • PTP1 B inhibitor therapy and the first anti-cancer therapy may be administered concomitantly or sequentially or in any therapeutically-effective dosage and/or administration regimen.
  • kits for monitoring progression of a cancer in a subject or response to treatment by a subject comprising reagents for detecting PTP1 B or measuring PTP1 B levels, and instructions for use of said reagents, wherein increased levels of PTP1 B indicate progression of cancer and/or lack of response to treatment, and decreased levels indicate that the cancer has not progressed and/or a positive response to anti-cancer treatment, i.e. treatment is efficacious.
  • kits for detecting or measuring overabundance of PTP1 B in cancerous cells comprising the steps of reacting RNA or protein contained in a clinical sample with a reagent, said clinical sample having been obtained from an individual suspected of having or known to have cancerous cells; and comparing the amount of complexes formed between the reagent and the RNA or protein in the clinical sample with the amount of complexes formed between the reagent and RNA or protein in a control sample.
  • the reagent may be any standard reagent which is specific for PTP1 B and known in the art for detecting PTP1 B RNA or protein, for example, PCR primers and reagents, antisense oligonucleotides, antibodies, etc.
  • the present invention encompasses a method of treating or preventing cancer in a subject in need of such treatment, comprising administering to said subject a therapeutically effective amount of an inhibitor of protein tyrosine phosphatase 1 B (PTP1 B).
  • PTP1 B protein tyrosine phosphatase 1 B
  • the invention relates to a method for treating or preventing breast cancer in a subject.
  • ErbB2-induced mammary tumorigenesis is inhibited by administration of PTP1 B inhibitors.
  • the methods of the invention may, for example, delay mammary tumor progression, decrease mammary tumor multiplicity, etc.
  • ErbB2 positive cancer is treated or prevented by PTP1 B inhibitors.
  • the invention relates to a method for treating or preventing a cancer associated with overexpression of PTP1 B.
  • the invention relates to a method for treating or preventing prostate cancer in a subject.
  • Non-limiting examples of cancers for treatment are selected from cancers of the breast, prostate, lung, ovary, brain, genitourinary tract, lymphatic system, stomach, and larynx.
  • Another set of forms of cancer are histiocytic lymphoma, lung adenocarcinoma, small cell lung cancers, pancreatic cancer, glioblastomas, leukemia and breast carcinoma. It is contemplated that any cancer which expresses high levels of PTP1 B may be treated or prevented by administration of PTP1 B inhibitors.
  • PTP1 B inhibitors for use in the methods of the invention may be small molecules, siRNA, antisense, antibodies, etc. Many PTP1B inhibitors are known in the art and may be used in the methods of the invention. For example, PTP1 B inhibitors are described in U.S. Patent numbers 7,199,121 ; 7,179,796; 7,169,797; 7,163,932; 7,163,952; 7,141 ,596; and 7,115,624, the entire contents of which are hereby incorporated by reference in their entirety.
  • a method for screening for anti-cancer therapeutics comprising determining whether an agent is an inhibitor of PTP1 B.
  • methods for identifying anti-cancer agents based on inhibition of PTP1 B are also provided.
  • PTP1B inhibitors in treating or preventing cancer, as described herein.
  • the present invention encompasses a method of treating or preventing cancer in a subject being treated with a first anti-cancer treatment, comprising administering to said subject a therapeutically effective amount of an inhibitor of protein tyrosine phosphatase 1 B (PTP1 B).
  • the first anti-cancer treatment may be surgery, radiology, chemotherapy, or a targeted cancer treatment. More specifically, the targeted cancer treatment is selected from the group consisting of small molecules, monoclonal antibodies, cancer vaccines, antisense, siRNA, aptamers and gene therapy.
  • the first anti-cancer treatment may be an anti-ErbB2 therapy.
  • the first anti-cancer treatment and the PTP1 B inhibitor may be administered concomitantly or sequentially.
  • Cancer is characterized by deregulated cell proliferation.
  • Cancer refers herein to a cluster of cancer cells showing over proliferation by non- coordination of the growth and proliferation of cells, without respect to normal limits, which may be due to the loss of the differentiation ability of cells, and which may invade and destroy adjacent tissues and may spread to distant anatomic sites through a process called metastasis.
  • the encompassed cancer is selected from the group consisting of breast cancer, prostate cancer, lung cancer, ovarian cancer, lymphoma, and their metastases.
  • Cancers of the brain, genitourinary tract, lymphatic system, stomach, and larynx and their metastases are also encompassed, as are histiocytic lymphoma, lung adenocarcinoma, small cell lung cancers, pancreatic cancer, glioblastomas and breast carcinoma and metastases thereof.
  • breast carcinomas including lobular and duct carcinomas, and other solid tumors, carcinomas, sarcomas, and cancers including carcinomas of the lung like small cell carcinoma, large cell carcinoma, squamous carcinoma, and adenocarcinoma, stomach carcinoma, prostatic adenocarcinoma, ovarian carcinoma such as serous cystadenocarcinoma and mucinous cytadenocarcinoma, ovarian germ cell tumors, testicular carcinomas, and germ cell tumors, pancreatic adenocarcinoma, biliary adenocarcinoma, heptacellular carcinoma, renal cell adenocarcinoma, endometrial carcinoma including adenocarcinomas and mixed Mullerian tumors (carcinosarcomas), carcinomas of the endocervix, ectocervix, and vagina such as adenocarcinoma and squamous carcinoma, basal cell carcinoma, melanoma
  • the encompassed cancer expresses PTP1 B.
  • the encompassed cancer expresses PTP1 B and one or more known oncogenic proteins, such as EGFRvIII, EGFR/HER-1/ErbB1 , ErbB2/HER-2, ErbB3/HER-3, ErbB4/HER-4, ras, myc, BRCA1 , and BRCA2.
  • expression of PTP1 B is elevated in the cancerous cells of a subject being treated.
  • Figure 1 illustrates the reduced rate of tumor development, number of tumors and lung metastases in NDL2-PTP1 B-/- mice.
  • A Kaplan-Meier kinetic analysis of tumor occurrence in NDL2-PTP1B female transgenic mice. In order to detect mammary tumors, mice were examined twice a week after weaning of the second litter. The curves were drawn and analyzed using Prism software.
  • the number of animals analyzed for each genotype (n) and the median time to tumor onset (T50) are also shown.
  • FIG. 2 illustrates the distinct mammary gland histopathology in NDL2-PTP1 B+/+ compared to NDL2-PTP1 B-/-.
  • the representative sections were obtained from the mice described in Supplementary Fig. 1 , respectively.
  • Arrows indicate mitotic figures (panels F-G).
  • Tissue section from a 3 month-old non-transgenic FVB mouse is presented as a control (panel A). Bar, 50/vm (panel A); 200 ⁇ m (panels B-E); 100 ⁇ m (panels F- G) and 20 ⁇ m (enlargement);
  • FIG. 3 illustrates the reduced expression levels of ErbB2 and ErbB3 in breast tumors of NDL2- PTP1 B-/- transgenic mice.
  • Breast tumor tissue (BT) was isolated from NDL2-PTP1 B+/+ and NDL2-PTP1 B-/- transgenic mice at week 0.3 (BT0.3), 4 (BT4), and 6 (BT6) after tumor occurrence.
  • Normal mammary epithelium adjacent to the tumors at week 6 after tumor onset normal breast, NB6 was used as a control.
  • ErbB2 was immunoprecipitated (IP) from breast tumor tissue lysates and immunoprecipitates were subjected to SDS-PAGE and immunoblot (IB) analysis was performed using anti- phosphotyrosine antibodies (4G10), followed by a reprobe with anti-ErbB2 antibodies. Phosphorylated-ErbB2 (P-ErbB2) and ErbB2 bands are indicated by the arrows at molecular weight 185 kDa. Mammary tissue from non-transgenic FVB mouse (lane 1 ) was included as a control for endogenous ErbB2 expression. The experiment was performed three times, using three mice per time point in total.
  • the diagram illustrates the densitometry analysis of the phosphorylated ErbB2/ErbB2 ratio obtained from all the experiments. Results represent the mean ⁇ SD. * P ⁇ 0.001 NDL2-PTP1 B+/+ versus NDL2-PTP1 B-/-.
  • B Breast tumor tissue (BT) lysates from NDL2-PTP1 B+/+ and NDL2-PTP1 B-/- transgenic mice were separated by 4-12% gradient SDS-PAGE and transferred to PVDF membrane. The membrane was blotted with anti-ErbB2 antibodies and reprobed with anti-ErbB3 antibodies. The anti-Grb2 immunoblot is used as a loading control. The experiment was repeated three times, using three mice per time point;
  • FIG. 4 illustrates the decreased Ras-MAPK signaling in breast tumors of NDL2-PTP1 B-/- mice.
  • Breast tumor tissue (BT) was isolated from NDL2-PTP1 B+/+ and NDL2-PTP1 B-/- transgenic mice at week 0.3 (BT0.3), 4 (BT4), and 6 (BT6) after tumor occurrence. Normal mammary epithelium adjacent to the tumors at week 6 after tumor onset (normal breast, NB6) was used as a control.
  • B p120RasGAP phosphorylation was analyzed by immunoprecipitating p120RasGAP, probing with anti- phosphotyrosine antibodies (4G10), and then reprobing with anti-p120RasGAP antibodies.
  • FIG. 5 illustrates the downregulation of Akt activation in NDL2- PTP 1 B-/- transgenic mice.
  • Breast tumor tissue (BT) was isolated from NDL2- PTP1 B+/+ and NDL2-PTP1 B-/- transgenic mice at week 0.3 (BT0.3), 4 (BT4), and 6 (BT6) after tumor occurrence.
  • Normal mammary epithelium adjacent to the tumors at week 6 after tumor onset (normal breast, NB6) was used as a control.
  • A 20 ⁇ g of the samples were analyzed for Akt protein and phosphorylation levels by using phosphospecific antibodies (anti-phosphoS473- Akt).
  • B and C p27 and Cyclin D1 expression levels were determined in the breast tumor samples described in (A).
  • Grb2 expression was used as a loading control.
  • FIG. 6 illustrates the increased apoptosis in breast tumor samples of NDL2-PTP1 B-/- mice.
  • A Western blot analysis of PARP expression and cleavage from breast tumor lysates from NDL2-PTP1 B+/+ and NDL2-PTP1 B-/- transgenic mice at 0.3 (BT0.3), 4 (BT4) and 6 (BT6) weeks after tumor occurrence. The full-length (113 kDa) and the cleaved fragments (85 kDa) are indicated by the arrows.
  • B lmmunoblot analysis was performed with anti- caspase-3 antibodies on breast tumor total lysates as described in (A).
  • Figure 7 illustrates the PTP1 B inhibitor administration delays the onset of mammary tumor development in NDL2-PTP1 B+/+ mice.
  • Kaplan-Meier kinetic analysis of tumor occurrence in NDL2-PTP1 B female transgenic mice that received the PTP1 B inhibitor or vehicle. Mice were examined twice a week after the end of treatment in order to detect mammary tumors. The curves were drawn and analyzed using Prism software. Logrank tests of survival plots of the data indicate a statistically significant difference between compound administered-NDL2-PTP1 B+/+ and vehicle-administered NDL2-PTP1 B+/+ (P ⁇ 0.001 ). The number of animals analyzed for each genotype (n) and the median time to tumor onset (T50) are indicated on the graph;
  • FIG. 8 illustrates the overexpression of PTP1 B in breast induces mammary gland tumorigenesis.
  • A Schematic diagram of the human PTP1B transgene. The unshaded region represents sequences within the pBSKK vector backbone. The transcriptional start site within the MMTV-LTR is illustrated by the lower arrow and the 5' non coding sequences derived from the MMTV-v-Has-Ras vector pA9 are illustrated by the shaded box. The boundaries of the cDNA PTP1 B wild-type (WT), and SV40 processing signals are shown by the appropriate arrows.
  • WT wild-type
  • SV40 processing signals are shown by the appropriate arrows.
  • Figure 9 shows prostate-specific antigen recurrence-free survival curves plotted using the Kaplan-Meier analysis and the log-rank test, wherein the lower curve (pink) illustrates survival for patients expressing a high level of PTP- 1 B in prostate tumors, and the upper curve (green) illustrates survival for patients expressing low levels of PTP- 1 B in prostate tumors.
  • the cut-off value of 1.29 (average intensity of staining) was used to assign patients to the High PTP1 B expression group (> 1.29) or the Low PTP1 B expression group ( ⁇ 1.29).
  • Supplementary Figure 1 illustrates the comparative pathology of breast tumors in NDL2-ptpn1-7- and NDL2-ptpn1 +/+ mice.
  • mammary whole mounts from MMTV-NDL2 mice containing either PTP1 B wild-type or homozygous mutants (Supplementary Fig. 1 ).
  • NDL2-ptpn1+/+ animals exhibited a number of nodular masses amongst hyperplastic and dysplastic tissue at 0.3 week after palpable tumor, whereas NDL2-ptpn1-/- mice only presented hyperplastic lobuloalveloar endbuds (Supplementary Fig. 1 B vs C).
  • both groups presented a severe altered branching, hyperplastic progression and neoplasia in the fat pad (Supplementary Fig. 1 D-E vs A).
  • all these features were less pronounced in the absence of PTP1 B (Supplementary Fig. 1 D-F vs E-G, respectively);
  • Supplementary Figure 2 illustrates the unaltered Src phosphorylation during mammary tumor progression in NDL2-ptpn1 null mice. Since numerous tumors and cell lines overexpressing ErbB2 show high levels of activated Src 19 and because previous in vitro studies have identified PTP1 B as a potent activator of Src by dephosphorylating its negative tyrosine regulatory site in human breast cancer cell lines 20, we examined the relative levels of Src activity and expression in breast tumor samples of our NDL2-ptpn1 wild-type and null animals (Supplementary Fig. 2). Tumor lysates were subjected to western blot analysis using phosphospecific antibodies against the inhibitory phosphorylation site of Src (Y529).
  • Supplementary Figure 3 shows that administration of PTP1 B inhibitor in NDL2-ptpn1 +/+ normalizes glucose levels. Glucose levels remains similar and lower than wild-type animals (5.71 ⁇ 0.13 mmol.L-1 ; P ⁇ 0.05, data not shown) in both PTP1 B inhibitor-administered NDL2-ptpn1 -7- group (4.40 ⁇ 0.09 mmol.L-1 ; P ⁇ 0.05) and vehicle-administered NDL2-ptpn1-7- group (4.35 ⁇ 0.12 mmol.L-1 ; P ⁇ 0.05) all over the 21-days treatment and further in time.
  • PTP1 B inhibitor administration lowered glucose levels in the NDL2-ptpn1 +/+ group between day-6 of treatment up to 10 days after the end of treatment with an average of 4.50 ⁇ 0.09 mmol.L-1 (P ⁇ 0.05) as compared to vehicle- administered NDL2-ptpn1+/+ group (5.58 ⁇ 0.17 mmol.L-1 ; P ⁇ 0.05)( Supplementary Fig. 3);
  • Supplementary Tablei illustrates a summary of phenotypic abnormalities in MMTV-PTP1 B transgenic mice.
  • Four different female funders (A, B C and D from a second generation F2) were bred to FVB male to induce pregnancy in order to activate MMTV promoter and to synchronize tumor occurrence.
  • Female were sacrificed after the weaning of the second, fifth or seventh pregnancy.
  • Tissue mammary gland were processed according to routine procedures and embedded in paraffin. Sections were cut and stained with H&E for histopathological diagnosis. A minimal diffuse mammary gland acinar hyperplasia was observed after 2 litters. However, after 5 or 7 litters mice developed mammary gland carcinoma papillary type.
  • This tumor is well differentiated and composed of numerous finger-like projections supported by a fibrovascular stroma and covered by neoplastic epithelium.
  • the rest of mammary gland was composed of hyperplastic acini, mild, with few mitoses and little atypia (nuclear pleomorphism).
  • the rest of the mammary gland was composed of hyperplastic acini, minimal, with few mitoses and little atypia (nuclear pleomorphism). All these data provide unambiguous evidence that PTP1 B transgene may drive tumors by its own.
  • PTPs were first postulated to be tumor suppressor genes.
  • the role of PTP1 B is unclear: PTP1 B protein levels have been found to be increased in an important proportion of breast and ovarian cancers, but decreased in the esophageal cancers. Our findings presented herein have revealed the oncogenic properties of PTP1 B.
  • PTP1 B-deficient fibroblasts display increased IGF-I receptor, PDGRF and EGFR tyrosine phosphorylation and associated PI3K-mediated signaling, but activation of their Ras/MAPK-mediated pathways is significantly impaired.
  • PTP1 B deficient -/- ErbB2 transgenic (TG) mice have normal pups and they are able to nurse their young to a normal weight.
  • PTP1 B WT and heterozygote ErbB2 transgenic animals have detectable tumors at 4 months of age, but knockout PTP1 B MMTV-ErbB2 animals have yet to develop tumors at the same age.
  • mice lacking PTP1 B or PTP1 B inhibitor- administered mice display ErbB2-induced breast tumor latency.
  • mouse mammary tumor virus (MMTV)-dependent over-expression of PTP1 B in mammary gland leads to spontaneous breast cancer development following multiple pregnancies.
  • MMTV mouse mammary tumor virus
  • tumor development was delayed by approximately 85 days in the NDL2- PTP1 B-/- strain compared to the NDL2-1 B+/+ mice.
  • the first palpable tumor in the NDL2-PTP1 B-/- strain occurred at 147 days of age and by day 230, 90% of the animals had developed tumors.
  • NDL2-PTP1 B+/- mice exhibited an intermediate profile of tumor occurrence, suggesting that the absence of one allele of PTP1 B is sufficient to delay the onset of breast tumor development by 35 days compared to NDL2-PTP1 B+/+ mice (Fig. 1A). These results indicate that the PTP1 B gene dosage is limiting for tumorigenesis.
  • mice were sacrificed at week 0.3, 4 and 6 after tumor occurrence and diagnosis of mammary tumorigenesis and tumor multiplicity was confirmed by visual examination following necropsy. Up to 4 weeks after tumor formation, there was no significant difference in tumor burden between the groups. However, 6 weeks after tumor occurrence, the NDL2-PTP1 B+/+ mice showed twice as many tumors (15 ⁇ 2) than the NDL2-PTP1 B-/- mice (6.7 ⁇ 1.8, PO.01 ) (Fig. 1 B). In addition to mammary tumor onset, the occurrence of lung metastatic lesions was also monitored. Whereas, all NDL2-PTP1 B+/+ mice, 4 weeks after breast tumor onset, developed lung metastases (Fig.
  • NDL2-PTP1 B+/+ tumor samples phospho-ErbB2 levels were detectable at the time of tumor onset (Fig. 3A upper panel, lane 5 versus 9) and higher than in NDL2-PTP1 B-/- tumor samples (Fig. 3A upper panel, lanes 6-7 versus 10-11 , P ⁇ 0.001 ). Since heterodimerization of ErbB receptors is crucial for cellular signaling and the ErbB2-ErbB3 receptor pair forms the most potent signaling module of the ErbB- receptor family in terms of cell growth and transformation 8 the kinetics of ErbB3 expression during breast tumor progression from 0.3 to 6 weeks was examined. Whereas, the ErbB3 and ErbB2 expression patterns were quite similar (Fig.
  • p62 Dok binds to p120RasGAP, resulting in inhibition of ERK activation 24 ' 25 .
  • p120RasGAP was immunoprecipitated from breast tumor lysates at different time point after tumor initiation (0.3, 4 or 6 weeks) and western blot analysis was performed using anti-phosphotyrosine antibodies.
  • Fig. 4B BT4 and BT6 samples display RasGAP phosphorylation, which inversely correlates with p62 Dok phosphorylation (Fig. 4A).
  • RasGAP phosphorylation was attenuated in the absence of PTP1 B compared to the wild- type samples (Fig. 4B lanes 7-8 versus 3-4, P ⁇ 0.005) and consistent with our previous data 18 there appeared to be decreased levels of RasGAP protein in the PTP1 B expressing samples compared to the PTP1 B deficient samples. Furthermore, when p42/p44 MAPK phosphorylation was examined in these same samples MAPK activation was totally inhibited in NDL2-PTP1B-/- breast tumor samples (Fig. 4C, lane 3 versus 6, P ⁇ 0.005). These results show that the absence of PTP1 B attenuated the Ras-MAPK-induced ErbB2 activation in breast tumor progression. Indeed, PTP1 B may act as a positive regulator downstream of ErbB2 at least through the downregulation of p62 Dok activity, leading to increased Ras and p42/p44 MAPK activation.
  • ErbB2-ErbB3 heterodimer has the capacity to signal very potently through Ras-MAPK for proliferation, but also through the PI3K/Akt pathway for survival 8 .
  • Akt is one of the most activated serine/threonine kinase in human cancer 26 and its activation occurs during ErbB2 overexpression.
  • NDL2-PTP1 B+/+ breast tumor samples as early as tumor initiation (0.3 weeks) and up to 6 weeks after tumor onset there was increased compared to normal adjacent mammary epithelium and sustained S473 Akt phosphorylation in all tumor samples (Fig 5A, lane 1 versus 3-5, P ⁇ 0.005). This was in contrast to the NDL2-PTP1B-/- samples which displayed an attenuated Akt phosphorylation level compared to NDL2-PTP1 B+/+ samples, and further decreased during breast tumor progression (Fig. 5A, lanes 6-8 versus lanes 3-5, P ⁇ 0.005).
  • cyclin D1 was overexpressed at the tumor initiation stage and up to 6 weeks after tumor occurence compared to control adjacent tissue (Fig. 5C, lanei and 4 versus lanes 2-3 and 5-6, respectively) 30 ' 31 .
  • the cyclin D1 protein levels showed a reciprocal response to p27 k ⁇ p , with elevated expression observed in absence of p27 k ⁇ p (Fig. 5B versus Fig. 5C).
  • cyclin D1 expression levels were significantly higher when PTP1 B was present (Fig. 5C, lanes 2-3 versus 5-6).
  • caspase-3 activation in these samples was also determined.
  • the 17 kDa activated caspase-3 cleavage product is increased in NDL2-PTP1 B-/- breast tumor samples 6 weeks following tumorigenesis onset compared to NDL2-PTP1 B+/+ samples (Fig. 6B, lane 6 versus 3), suggesting a higher number of apoptotic events in breast tumor in the absence of PTP1 B.
  • PTP1 B plays a critical and positive role in human related ErbB2-induced breast cancer and suggest that inhibition of this enzyme may be beneficial in the treatment of this disease.
  • PTP1 B inhibition would provide the same delay in tumorigenesis as was observed for the PTP1 B genetic deficiency a specific orally available PTP1 B inhibitor 33 was used to treat NDL2-PTP1B transgenic mice. The effect of PTP1 B inhibition in these animals was monitored by measurement of glucose levels during the 21 days of treatment. It is known that PTP1 B deficiency results in enhanced insulin sensitivity and decreases in blood glucose levels.
  • NDL2 transgenic mice with the PTP1 B inhibitor resulted in blood glucose lowering during the time course of treatment comparable to the levels observed in the NDL2-PTP1 B-/- mice.
  • Treatment of NDL2-PTP1B-/- mice with the compound had no effect on blood glucose levels suggesting specific target engagement (Supplementary Fig. 3).
  • the first palpable tumor in the PTP1 B inhibitor-administered NDL2-PTP1 B+/+ group occurred 48 days after the end of treatment and 20 days later, 90% of the animals had developed tumors, with a significant delay of approximately 29 days compared to the vehicle-administered NDL2-1 B+/+ mice. Two mice still remained tumor-free after more than 75 days after the end of treatment.
  • transgenic mice were generated in which wild-type PTP1 B, fused to enhanced green fluorescent protein (EGFP), was expressed specifically in the mammary gland (Fig. 8A).
  • EGFP enhanced green fluorescent protein
  • Transgenic protein expression was directly correlated to the increased numbers of litters (Fig. 8B, lane 2 versus lanes 1 and 4) and was also concomitant to a dramatic increased in endogenous PTP1 B protein levels (Fig. 8B, lane 2 versus lanes 1 and 4) and to mammary gland transformation (Fig. 8C).
  • Supplementary Table 1 summarizes the phenotypic abnormalities derived from 4 different mouse lines.
  • NDL2-PTP1 B-/- mice are resistant to lung metastasis and the effects may cumulate through the regulation of cyclin D1 expression, as well as apoptosis triggered by the down-regulation of MAPK and AKT signaling pathways.
  • NDL2-PTP1 B null mice The induction of the cell-death pathway in NDL2-PTP1 B null mice is an important feature since it could be combined to chemotherapy in the treatment of breast cancer. For instance, resistance to chemotherapy-induced apoptosis could be overcome by blocking the anti-cell death pathway with a PTP1 B inhibitor. Interestingly, ablation of PTP1 B has no consequences on adult mouse physiology, suggesting that anti-PTP1 B therapy might be highly selective in preventing breast tumorigenesis. Moreover, since NDL2-PTP1 B-/- animals are resistant to lung metastasis, shorter treatments with a PTP1 B inhibitor should be investigated in clinical studies in patients suffering of breast cancer.
  • PTP1 B expression in prostate tumor sections from human prostate cancer patients was assessed using immunohistochemistry. Progression of disease in the patients was also assessed by measuring PSA levels in the samples, where a PSA increase above 0.3 ng ml 1 was defined as postoperative recurrence of the disease. It was found that elevated PTP1 B expression in prostate tumors correlates with disease recurrence as measured by PSA levels, Gleason grade, Extracapsular invasion, seminal vesicle invasion and survival functions, as shown in Tables 1 and 2 below and in Figure 9.
  • Table 1 indicates correlations between PTP1 B staining intensity in tumors and clinico-pathological parameters.
  • Table 2 indicates correlations between PTP1B staining intensity in normal tissues and clinico-pathological parameters. This data shows a strong correlation between elevated PTP1B expression in prostate tumors and prostate cancer.
  • Figure 9 shows prostate-specific antigen recurrence-free survival curves plotted using the Kaplan-Meier analysis and the log-rank test, wherein the lower curve (pink) illustrates survival for patients expressing a high level of PTP- 1 B in prostate tumors, and the upper curve (green) illustrates survival for patients expressing low levels of PTP- 1 B in prostate tumors.
  • PTP1 B +/' and ⁇ ' ⁇ mice were generated as previously described 35 and were backcrossed with FVB/J wild-type mice for seven generations to introduce the targeted PTP1 B alleles onto a FVB background.
  • ErbB2/neu transgenic (TG) mice have been generated in FVB strain by the expression of a neu deletion mutant (NDL2) cDNA under the transcriptional control of the MMTV-LTR 6 ' 7 .
  • mice were interbred to generate females of the required genotypes: NDL2-PTP1 B +/+ (ErbB2/neu TG- WT PTP 1 B-), NDL2- PTP1B +/- (ErbB2/neu TG- heterozygous PTP1B), and NDL2-PTP1B -7- (ErbB2/neu TG- null PTP1 B).
  • Genotypes for PTP1 B and Neu were determined by Southern blot and PCR analysis respectively 7 ' 35 . Mice were kept on a 12h light/12h dark cycle and were allowed free access to food and water. Animals were monitored daily for physical well-being and were examined twice a week for tumor occurrence.
  • mice We generated MMTV_EGFP_PTP1B transgenic mice by microinjecting the linearized expression construct into the pronucleus of FVBN mouse embryos at day 0.5 p.c. Injected embryos were implanted into pseudopregnant CD-1 female mice. Progenies were screened by PCR of tail biopsies. Mice positive for the transgene were mated to WT FVBN mice. All procedures were carried out according to the Canadian Council on Animal Care ethical regulations and were approved by the McGiII University Research and Ethics Animal committee.
  • PTP1 B inhibitor was synthesized at Merck Frosst Canada Ltd., and the methods of synthesis have been described 33 .
  • PTP1 B compound was administered (30 mg/kg body weight) daily by oral gavage with an injection volume of 10 ml/kg body weight for 21 days.
  • Vehicle solution consisted of 0.5% methylcellulose (Sigma Aldrich). Solutions were freshly prepared before each administration. Mice were sacrificed 10 days after tumor occurrence.
  • Tissue samples were ground into a powder under liquid nitrogen and lysed for 30min on ice in a modified TLCK lysis buffer (50 mM HEPES pH 7.4; 10% Glycerol; 1 % Triton X-100, 150 mM NaCI; 1 mM EGTA, pH 8.0; 1 mM sodium orthovanadate; 20 mM NaF; Complete EDTA-free protease cocktail inhibitors).
  • the cell lysates were cleared by centrifugation at 12,000 g for 15min at 4°C.
  • Total mammary gland lysates (200 ⁇ g) were incubated with 20 ⁇ of protein A-Agarose and with 2//g of anti-ErbB2 antibody for 3h, rotating at 4C° in 400 ⁇ of modified TLCK lysis buffer. After five washes with the lysis buffer, precipitated proteins were released by boiling in sample buffer and then subjected to western blot analysis.
  • Inguinal mammary glands number four were dissected and spread onto glass slides. Samples were fixed overnight in acetone and then stained for 24 hours in Modified Harris Hematoxilin. After several washes in 1 % HCI/70% ethanol, samples were cleared overnight in xylene and mounted with permount. Samples were examined under a dissecting microscope.
  • Biochemical recurrence-free survival was defined as the time between date of surgery and the date of first PSA increase above 0.3 ng/ml 1.
  • the final staging, grading and histologic diagnosis was based on the Hospital Notre-Dame (Montreal, QC, Canada) pathology report in agreement with the review from an independent pathologist.
  • Ethics approval was obtained from the local IRB committee.
  • PTP1 B expression in prostate tumor sections was assessed using the polyclonal Rabbit Anti-human PTP1 B Antibody AF1366 (R&D Systems, Minneapolis, MN). lmmunostaining was performed using the biotin-streptavidin- peroxydase method. Briefly, formalin-fixed paraffin-embedded sections were deparaffinized in toluene and rehydrated through graded ethanol followed by distilled water. Antigen retrieval was done heating slides in the microwave for 15 minutes in citrate buffer (pH 6,0). Non specific sites were blocked with goat serum and slides were then incubated with the primary antibody at a 1/300 dilution for 2 hrs at room temperature.
  • Endogenous peroxydase was quenched in 3% hydrogen peroxide.
  • a biotinylated goat anti-rabbit secondary antibody followed by streptavidin-HRP (Lab Vision, Fremont, CA) were applied for 20 minutes each. All rinsing steps between antibodies were done in PBS-T for 5 minutes. Chromogen reaction using a 3,3'-diaminobenzidine tetrahydrochloride (DAB) solution kit (Lab Vision, Fremont, CA) was carried out for 5 minutes. Slides were counterstained with Harris Hematoxylin for 10 seconds, dehydrated in ethanol and toluene and then mounted.
  • DAB 3,3'-diaminobenzidine tetrahydrochloride
  • Tumour sections were inspected at 2Ox and 4OX magnification. Epithelial zones were scored according to the intensity of staining of the cytoplasm (value of 0 for absence, 1 for weak, 2 for moderate, 3 for high intensity). In cores where staining was of variable intensity the average intensity was reported. The Spearman and Pearson correlation coefficient tests (two tailed) were used to estimate the correlation with clinicopathologic variables. Prostate-specific antigen recurrence-free survival curves were plotted using the Kaplan-Meier analysis and the log-rank test was used to test for significant differences. Receiver operative characteristic (ROC) curves were used to determine the threshold value.
  • ROC Receiver operative characteristic
  • ErbB2 potentiates breast tumor proliferation through modulation of p27(Kipl)-Cdk2 complex formation: receptor overexpression does not determine growth dependency.

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Abstract

Le rôle de la protéine tyrosine phosphatase 1B (PTP1B) dans la tumorigenèse mammaire a été étudié en utilisant des approches génétiques et pharmacologiques. La délétion de l'activité PTP1B dans les souris transgéniques NDL2, soit par reproduction avec des souris déficientes en PTP1B, soit par traitement avec un inhibiteur de PTP1B spécifique, conduit à une latence de tumeur mammaire significative et à une résistance à une métastase de poumon. A l'inverse, une surexpression spécifique de PTP1B dans la glande mammaire conduit à un développement spontané du cancer du sein. La régulation de la tumorigenèse mammaire induite par ErbB2 par PTP1B a lieu par l'atténuation à la fois des voies MAPK et AKT. Nous rapportons ici que PTP1B est un nouveau marqueur et une nouvelle cible thérapeutique pour le cancer, par exemple dans le cancer du sein, le cancer de la prostate, le cancer du poumon, le cancer des ovaires, le lymphome et leurs métastases.
PCT/CA2008/001627 2007-09-14 2008-09-15 Protéine tyrosine phosphatase 1b et cancer WO2009033293A1 (fr)

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CN105753753A (zh) * 2016-04-12 2016-07-13 复旦大学附属华山医院 一类调节雌激素相关受体活性的化合物及其医学用途
TWI723030B (zh) * 2015-07-01 2021-04-01 長庚醫療財團法人嘉義長庚紀念醫院 二氫異丹蔘酮ｉ於治療癌症之用途
US11406647B2 (en) 2017-11-06 2022-08-09 Cold Spring Harbor Laboratory Method and compositions for forming a copper-containing complex and uses thereof

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WO2003070881A2 (fr) * 2002-02-20 2003-08-28 Sirna Therapeutics, Inc. Inhibition de l'expression genique de la proteine typrosine phoshatase-1b (ptb-1b) induite par l'interference arn, utilisant un acide nucleique d'interference court (sina)

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WO2003070881A2 (fr) * 2002-02-20 2003-08-28 Sirna Therapeutics, Inc. Inhibition de l'expression genique de la proteine typrosine phoshatase-1b (ptb-1b) induite par l'interference arn, utilisant un acide nucleique d'interference court (sina)

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Cited By (3)

* Cited by examiner, † Cited by third party
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TWI723030B (zh) * 2015-07-01 2021-04-01 長庚醫療財團法人嘉義長庚紀念醫院 二氫異丹蔘酮ｉ於治療癌症之用途
CN105753753A (zh) * 2016-04-12 2016-07-13 复旦大学附属华山医院 一类调节雌激素相关受体活性的化合物及其医学用途
US11406647B2 (en) 2017-11-06 2022-08-09 Cold Spring Harbor Laboratory Method and compositions for forming a copper-containing complex and uses thereof

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