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Altered Intracellular Localization of BRK/Sik Protein Tyrosine Kinase in Human Prostate Tumors

a technology of tyrosine kinase and human prostate cancer, which is applied in the field of animal detection methods of abnormal prostate conditions, can solve the problems of ineffective methods, large deleterious side effects, and difficult treatment of prostate cancer

Inactive Publication Date: 2007-02-15
THE BOARD OF TRUSTEES OF THE UNIV OF ILLINOIS
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0013] In another aspect, the inventive method can be used, for example, for pre-screening biopsies to determine if further analysis by a pathologist is necessary. A non-pathologist, such as a technician, can cost effectively perform a method of the invention and select candidate samples that require further analysis by a pathologist,

Problems solved by technology

Although a considerable amount of research has been devoted to developing effective therapies against the disease, prostate cancer remains difficult to treat.
However, these methods are ineffective in a significant number of cases and have a great many deleterious side effects.
Two previously identified prostate specific proteins, prostate specific antigen (PSA) and prostatic acid phosphatase (PAP), have been identified and used as markers for identifying patients with or at risk for prostate cancer, The therapeutic and diagnostic potential of PSA and PAP, however, is limited, For example, PSA levels do not always correlate with the presence of prostate cancer In some cases, elevated PSA levels are associated with a number of non-prostate cancer disorders, including benign prostatic hyperplasia (BPH).
Furthermore, PSA measurements correlate with prostate volume, an unreliable marker for prostate cancer, and do not indicate the level of metastasis.
The sensitivity of the DRE is limited, because the examining finger can only palpate the posterior and lateral portions of the gland, leaving some tumors undetected.
A pathologist assigns one number based on the level of differentiation of the most prevalent grade in the sample, and makes a second assessment based on the predominant secondary grade, The two grades are added together to get the “Gleason sum,” While the Gleason system is widely used, it often leads to variable scores between different diagnosticians, Poor reproducibility between diagnosticians is a major problem in grading prostate tumors.
The screening methods for detecting and diagnosing prostate tumors discussed above are limited in their sensitivity.

Method used

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  • Altered Intracellular Localization of BRK/Sik Protein Tyrosine Kinase in Human Prostate Tumors
  • Altered Intracellular Localization of BRK/Sik Protein Tyrosine Kinase in Human Prostate Tumors
  • Altered Intracellular Localization of BRK/Sik Protein Tyrosine Kinase in Human Prostate Tumors

Examples

Experimental program
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example 1

BRK Expression in the Nuclei of Normal Human and Mouse Prostate Secretory Epithelial Cells

[0046] Expression of breast tumor kinase (BRK) and its mouse ortholog, Sik, was examined in sections of adult human and mouse prostate, respectively, using immunohistochemistry (FIG. 1). Ventral mouse prostates were surgically removed, fixed in 4% paraformaldehyde in phosphate buffered saline (PBS) overnight at 4° C., and washed in 70% ethanol, The tissues were then processed for paraffin embedding by passage through 70% ethanol for 1 hour (two times), 95% ethanol for 1 hour (three times), 100% ethanol for 1 hour (three times), xylene for 1 hour (two times), and liquid paraffin embedding medium (Fisher Scientific) at 62° C. for 1 hour (two times). The tissues were then mounted in paraffin blocks. Human prostate tissue samples were prospectively collected at the time of surgery for radical prostatectomy at Michael Reese Hospital, Chicago, Ill., in accordance with IRB guidelines, and embedded i...

example 2

BRK Localization is Altered in Poorly Differentiated Prostate Tumors

[0049] Fifty-eight individual paraffin embedded human prostate surgical samples were graded according to Gleason's microscopic grading system by a board-certifled pathologist. Gleason's system involves histologic grading based on the pattern of glandular formation, assigning a number of 1 to 5. Lower numbers are well differentiated and higher numbers are poorly differentiated (Gleason & Mellinger, 1974, J. Urol. 111:58-64). Among the samples examined, normal, benign, preneoplastic, and malignant conditions were observed. Sections from each surgical sample were stained with anti-BRK antibodies and two individuals analyzed the sections by scoring at least three fields per slide using light microscopy. The intensity of BRK nuclear staining was given a score on a scale from 1 to 100%, with 100% representing the intensity as displayed in the normal glands, since they displayed uniform intensity throughout their luminal...

example 3

Localization of San68 is Unaltered-in High Grade Prostate Tumors

[0053] Since BRK localization changes as tumors dedifferentiate, the localization of Sam68, a substrate of BRK, was also examined to determine if the state of differentiation affected Sam68 localization. Sam68 was localized in human and mouse prostate using immunohistochemistry as described above. Sam68 was detected in nuclei of luminal epithelial cells in both human and mouse prostate (FIG. 5A). Sections from the same tumor tissue blocks used to study BRK localization above were stained with anti-Sam68 antibodies and examined by light microscopy. While BRK showed loss of nuclear localization in the less differentiated tumors, Sam68 localization was unchanged in the BPH, PIN, and tumor samples compared with its expression pattern in normal tissues. FIG. 5B shows Sam68 and BRK (localization a Gleason grade 4 tumor and in PIN.

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Abstract

The invention provides methods for detecting abnormal prostate conditions, such as benign prostatic hyperplasia (BPH), prostatic intraepithelial neoplasia (PIN), and adenocarcinoma, in an animal by comparing the amount of the Breast Tumor Kinase (BRK) tyrosine kinase in the nuclei of prostate luminal epithelial cells in a test sample with an amount of nuclear BRK protein in epithelial cells of normal prostate glands.

Description

[0001] This application is related to U.S. provisional application Ser. No, 60 / 347,720, filed Jan. 11, 2002.[0002] This invention was made with government support under DK44525 and DK068503 awarded by the National Institutes of Health. The government has certain rights in the invention.FIELD OF THE INVENTION [0003] The invention relates to methods for detecting an abnormal prostate condition in an animal, Specifically, the invention relates to methods of detecting an abnormal prostate condition in an animal by detecting the amount of Breast Tumor Kinase (BRK) protein present in the nuclei of prostate luminal epithelial cells within a prostate tissue sample compared with the amount of BRE protein in the nuclei of normal prostate luminal epithelial cells. The invention further relates to methods for detecting prostate cancer in an animal by identifying prostate tissue samples wherein luminal epithelial cells in the sample do not display BRK nuclear localization BACKGROUND OF THE INVEN...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): G01N33/574C12Q1/48C12Q1/68
CPCC12Q1/485G01N33/57434C12Q2600/158C12Q1/6886
Inventor TYNER, ANGELADERRY, JASON J.
Owner THE BOARD OF TRUSTEES OF THE UNIV OF ILLINOIS
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