KR20090116336A - Method and composition for detecting hccr-1 expression level to prognose estrogen receptor positive, progesterone receptor positive, p53 tumor suppressor gene mutation and her2-positive breast cancer - Google Patents

Abstract

PURPOSE: A method for detecting expression of HCCR-1(Human cervical cancer oncogene) from a sample of patient is provided to predict prognosis of breast cancer. CONSTITUTION: A detection of HCCR-1 expression is performed by detecting the expression of HCCR-1 mRNA(messenger RNA). In the detection of HCCR-1 expression, an antibody which specifically binds to HCCR-1 protein is used. A therapeutic method of HER2 positive breast cancer comprises administration or chemotherapy of HER2 inhibitor.

Description

METHOD AND COMPOSITION FOR DETECTING HCCR-1 EXPRESSION LEVEL TO PROGNOSE ESTROGEN RECEPTOR POSITIVE, PROGESTERONE RECEPTOR POSITIVE, P53 TUMOR SUPPRESSOR GENE MUTATION AND HER2-POSITIVE BREAST CANCER}

The present invention relates to methods, compositions and kits for detecting expression levels of HCCR-1 for predicting prognosis of breast cancer. More specifically, the present invention detects the expression level of HCCR-1 from a patient's sample to provide useful information for predicting estrogen receptor positive, progesterone receptor positive, p53 tumor suppressor gene mutation, and HER2 positive type breast cancer prognosis and treatment choice. To methods, compositions and kits used therein.

The primary cancer protein HCCR-1 acts as a negative regulator of p53 and causes breast cancer. Cells expressing HCCR-1 form tumors in nude mice. The primary cancer gene acts as a negative regulator of p53 tumor suppressor in the tumor formation process (Ko J, Lee et al. Oncogene 2003, 22: 4679-4689). Northern and Western blot analysis and immunohistochemistry studies indicate that HCCR-1 mRNA and protein are overexpressed in breast cancer tissues compared to normal breast tissues (Ko J. Lee et al, supra, Jung SS et al, Clin Can Res) 2005, 11: 7700-08). As a result of serological studies, breast cancer showed 86.8% sensitivity to HCCR-1, which is higher than 21.0% sensitivity to CA 15-3 (Jung SS et al, supra and Lamerz R et al. In Vivo). (Athens) 1993, 7: 607-614). Thus, HCCR-1 analysis is advantageous over CA 15-3 for diagnosing breast cancer. These results indicate that HCCR-1 is a primary cancer protein involved in breast cancer development (Ko J. Lee et al, Jung SS et al, supra). However, there is no known mechanism for HCCR-1 to develop human breast cancer. There is no bar.

Overexpression of human epidermal growth factor receptor type 2 (HER2, HER / neu or ErbB2) (Schechter AL et al., Nature 1984, 312: 513-516), the first known 185-kD size receptor, more than 20 years ago, is an invasive breast cancer. In 20-30% of the time. As such, breast cancer when the HER2 receptor is overexpressed is particularly referred to as HER2-positive breast cancer. In general, patients who overexpress the receptor or have breast cancer cells with a high copy number of the gene have reduced overall survival compared to other types of breast cancer patients and respond specifically to several chemotherapy and hormonal agents (Ellis MJ et al. , J Clin Oncol 2001, 19: 3808-3816, Menard S et al., J Clin Oncol 2001, 19: 329-335). Therefore, strategies for targeting HER2 are considered important in the treatment of breast cancer (Hudis CA et al., J Med 2007, 357: 39-51). HER2 signaling promotes cell proliferation via the RAS-MAPK pathway and cell death via the phosphatidylinositol 3'-kinase-AKT-mammalian target of the rapamycin (mTOR) pathway. Inhibit (Yarden Y and Sliwkowski MX, Cell Biol 2001, 2: 127-137). Similarly, HCCR-1 signal is also known to be regulated by the phosphatidylinositol 3'-kinase-AKT pathway (Cho GW et al. Gene 2006, 384: 18-26).

According to our previous studies using a panel of breast cancer cell lines (Jung SS et al, supra), except for some that express ER / PR with a modified p53, HCCR-1 is a high HER2 level breast cancer. Highly expressed in cell lines (Bacus SS et al., Breast Dis 1999, 11: 63-75; Borresen-Dale AL, Hum Mutat 2003, 21: 292-300; Colditz GA et al. J Natl Cancer Inst 2004, 96: 218-228; and Slamon DJ et al., Science 1987, 235: 177-182). This data shows that HCCR-1 overexpression in breast cancer correlates highly with other known breast cancer prognostic markers.

Since HER2 overexpression and amplification have important consequences for predicting and treating breast cancer prognosis, the presence of HER2 must be accurately measured. Currently, worldwide, immunohistochemistry (immunohistochemistry: IHC) and fluorescence in situ hybridization (fluorescence in There are two different methods called situ hybridisation (FISH). Both of these techniques identify different targets and each have advantages and disadvantages. Further discussion is needed as to which method can be seen as a standard for HER2 measurements. Recently, other methods have been known that could be an alternative to HER2 testing. Real time polymerase chain reaction (RT-PCR) (Suo Z et al., Int J Surg Pathol 2004, 12: 311-318) and chromogen in situ hybridisation (CISH) (Raab G et al., J Clin Oncol) 2004, 22:14) are less expensive and are proposed as an alternative to FISH. Acceptable correlations have been reported between the two methods and FISH (Demonty G et al., Eur J Cancer 2007, 43: 497-509). However, the correlation between the various clinical methods of measuring HER2 is still incomplete for prognostic and predictive use of response to trastuzumab (Herceptin, Genentech).

Numerous studies have shown that trastuzimab is a therapeutic for HER2 positive tumors and results in markedly improved disease-free survival and overall survival (Tsuda H, Breast Cancer 2006, 13: 236-248, Viani GA et. al., BMC Cancer 2007, 7: 153). Only patients whose tumors show strong HER2 expression by immunohistochemical staining (IHC) and / or those who show amplification of the cerb2 gene by FISH are more likely to respond to Herceptin treatment. (Mass RD et al., Clin Breast Cancer 2005, 6: 240-246). Trastuzumab is a monoclonal antibody that targets HER2 clinically and is therefore only effective in breast cancer when HER2 receptors are overexpressed.

Because of the predictability of prognostic predictability and responsiveness to trastuzumab, testing for HER2 expression / gene proliferation in invasive breast cancer has become the standard of clinical practice. Many of the recent literature focuses on the best way to document HER2 overexpression (IHC vs. FISH), the technical limitations of each method, and the need for consistency and quality assurance in test performance. The National Comprehensive Cancer Network HER2 test of the Breast Cancer Task Force concluded that IHC or FISH would be acceptable if proper quality control / quality verification procedures were followed (Carlson RW et al., J Natl Compr Canc Netw). 2006, 3 (Suppl): S1-22).

Whether you use IHC with FISH in the lab or FISH as your initial HER2 screen, these tests are expensive. Developing a rational approach to screening cases for HER2 testing will improve the cost-effectiveness of healthcare systems (Haines GK 3rd et al., Breast Cancer Res Treat 2008, Jan 18 [online publication before print publication]). The present invention seeks to provide methods, compositions and kits for providing useful information in predicting breast cancer prognosis and selecting treatment methods that meet the problems and needs of such existing methods.

We found that levels of HCCR-1 in real breast cancer tissues correlated very well with known breast cancer prognostic markers such as ER / PR expression, p53 mutations and HER2 levels, including ER, PR, p53 and HER2. The invention has been completed by revealing the utility of using HCCR-1 expression as another new prognostic marker in combination with known prognostic parameters to predict breast cancer prognosis.

(Summary of invention)

Accordingly, the present invention provides a method for detecting the expression level of human cervical cancer oncogene (HCCR-1) from a patient's sample to provide information necessary for predicting the prognosis of HER2 positive breast cancer. It provides a method for detecting the expression level of HCCR-1, characterized in that the screening for receptor positive, progesterone receptor positive, p53 tumor suppressor gene mutation and HER2 positive.

In another aspect the invention provides a composition for predicting prognosis of HER2 positive breast cancer comprising an antibody that specifically binds HCCR-1 protein, and in another embodiment the invention specifically hybridizes to HCCR-1 mRNA Provided is a composition for predicting prognosis of breast cancer that is HER2 positive, comprising an oligonucleotide.

In another aspect, the present invention provides a kit for predicting prognosis of HER2 positive breast cancer, comprising an antibody specifically binding to HCCR-1 protein, and a binding detection means, and in another embodiment, the present invention is directed to HCCR-1 mRNA. Provided are a kit for predicting prognosis of HER2 positive breast cancer comprising specifically hybridizing oligonucleotides and hybridization detection means.

Hereinafter, the present invention will be described in more detail through embodiments.

Composition of the Invention

In one embodiment, the present invention provides a method for detecting the expression level of HCCR-1 from a sample of a patient in order to provide information necessary for predicting the prognosis of HER2 positive breast cancer. It provides a method for detecting the expression level of HCCR-1, characterized in that the screening. The method used for detecting the expression level of HCCR-1 is apparent to those skilled in the art. The expression level of HCCR-1 of the present invention may be achieved by detecting HCCR-1 mRNA expression. The expressed mRNA can be detected using conventional detection methods, including Northern blots, and tested for expression compared to the control tissue using normal tissue or the corresponding tissue of a non-breast cancer patient. Real time PCR (RT-PCR) methods and the like may also be used to more accurately and simply quantify the expression level of mRNA. In situ hybridization and immunohistochemistry using the same may be generally used as a method for identifying the expressed mRNA at its location in the tissue.

In addition, detecting the expression amount of HCCR-1 may be made by a method of detecting HCCR-1 protein expression using an antibody that specifically binds to HCCR-1 protein. Protein detection methods using antigen-antibody reactions between HCCR-1 proteins and antibodies specifically binding thereto are also apparent to those skilled in the art. Representative methods that can be used include, but are not limited to, Western blots, immunoprecipitation and ELISA and variations thereof.

Prognostic prediction of HER2 positive breast cancer in the methods of the present invention includes determining whether to use a HER2 positive breast cancer specific therapy. Breast cancer specific therapies that are HER2 positive in the methods of the invention may be administration or chemotherapy of inhibitors of HER2 expression or inhibitors of HER2 action. It can be used to determine whether to administer antibody therapeutics such as Trastuzumab or Lapatinib, which are widely used for the treatment of HER2 positive breast cancer, or whether to use various chemotherapy specific to HER2. . The method may also be used to determine whether to use any breast cancer treatment method that targets HER2 and to predict prognosis.

In another embodiment, the present invention provides a method for detecting HCCR-1 expression in a patient's sample, comparing the expression level of HCCR-1 with the expression level of HCCR-1 from the patient's sample. The present invention provides a method for diagnosing HER2 positive breast cancer, which includes determining an overexpression when the expression level is significantly high, and determining a patient determined as an HER2 positive test subject for HCCR-1 overexpression. The standard expression level of HCCR-1 used in the method of the present invention can be calculated by detecting the expression level of HCCR-1 from a corresponding sample of a patient not suffering from breast cancer. Preferably, the expression level standard level of HCCR-1 is calculated using a statistical method from a plurality of samples. In addition, the standard amount of expression level of HCCR-1 may be preferably detected from a sample before the onset of the same patient.

The HER2 positive breast cancer diagnosis method of the present invention can be used in combination in a manner performed before or after the performance of the conventional HER2 positive breast cancer diagnosis method. Preferably, the method of the present invention is used before performing a conventional diagnostic method as a means for determining whether to perform another diagnostic method. Diagnostic methods that can be used in combination with the methods of the invention include, but are not limited to, IHC, FISH, real time PCR, CISH, Western blot, and ELISA assays.

Furthermore, the diagnostic method of the present invention can be used to determine the treatment method and predict the prognosis of patients diagnosed as HER2 positive breast cancer by the diagnostic method of the present invention alone or in combination with other methods of the present invention. Breast cancer specific therapies that are HER2 positive may be administration or chemotherapy of inhibitors of HER2 expression or inhibitors of HER2 action. In particular, it can be usefully used to determine the administration of antibody therapeutics such as Trastuzumab or Lapatinib or the use of various chemotherapy specific to HER2.

In one aspect, the present invention provides a composition for predicting prognosis of HER2 positive breast cancer comprising an antibody that specifically binds to HCCR-1 protein. As the antibody specifically binding to the HCCR-1 protein, monoclonal antibodies or polyclonal antibodies can be used as necessary. Monoclonal antibodies or polyclonal antibodies can be readily prepared using any general technique well known to those skilled in the art.

In another aspect, the present invention provides a kit for predicting prognosis of HER2 positive breast cancer, comprising an antibody specifically binding to HCCR-1 protein and a binding detection means. As a means of detecting antigen-antibody binding, it is generally adopted to visualize a label attached to a secondary antibody. Generally used labels include, but are not limited to, radioisotopes, the use of enzymes including luciferase, and the like.

In another aspect, the present invention provides a composition for predicting prognosis of HER2 positive breast cancer, comprising an oligonucleotide that specifically hybridizes to HCCR-1 mRNA. Oligonucleotides that specifically hybridize to HCCR-1 mRNA can readily utilize complementary fragments of suitable length for use in specific hybridization by targeting the HCCR-1 mRNA sequence. Oligonucleotide designs for this use are apparent to those skilled in the art.

In another aspect, the present invention provides a kit for predicting prognosis of breast cancer that is HER2 positive comprising oligonucleotides that specifically hybridize to HCCR-1 mRNA and hybridization detection means. Hybridization detection means are generally labeled with radioisotopes or enzymes, and then detected using autoradiographs or specific substrates of enzymes, but any method that can be used for such a purpose can be used.

Using methods, compositions and kits for detecting the expression level of HCCR-1 of the present invention can more accurately and accurately predict the prognosis of HER2 positive type breast cancer in terms of cost and procedure compared to conventional methods, and is useful for selecting treatment methods. Can be provided.

Specific embodiments of the present invention will be described through the following examples. Other embodiments within the scope of the invention disclosed herein are also apparent to those skilled in the art in view of the present specification or the prior art in the art. The embodiments described below are only described for illustrative purposes, and the scope of the present invention is limited only by the claims.

<Example>

Tissues and Cell Lines

Tissues and cell lines used in the examples below are as follows.

Human normal and cancerous tissues were obtained during surgery. All patients received individual consent for the study. The use of tissue samples was approved by the Ethics Committee of the Catholic University of Medicine. Mammalian cell lines were obtained from the American Type Culture Collection (ATCC; Manassas, VA). BT-474, MCF-7 and MDA-MB-231 are mammary gland derived human breast cancer cell lines. MCF-7 and MDA-MB-231 cells express HER2 at low levels and BT-474 cells express HER2 at high levels. BT-474 and MCF-7 cells are ER-positive and PR-positive cells. MCA-MB-231 is an ER-negative and PR-negative cell line. MCF-7 cells have wild type p53 and MDA-MB-231 and BT-474 cells have mutated p53.

Example 1: Northern blot analysis to investigate the expression level of HCCR-1 in breast cancer

Total RNA was extracted from fresh human tissues and cell lines using the RNeasy total RNA kit (Qiagen). 20 μg of total RNA denatured in 1.0% formaldehyde agarose gel was electrophoresed and transferred to nylon membrane for Northern blot analysis. Human β-actin cDNA control probe was used as loading control.

The expression pattern of HCCR-1 in human normal tissue, cancer tissue and cell line was investigated. Northern blot analysis showed that primary breast cancer tissues showed increased HCCR-1 expression compared to normal tissues (FIG. 1). HCCR-1 was abundantly detected in BT-474 (ER + / PR + / mutant p53 / high HER2) cells but not in MDA-MB-231 (ER- / PR- / p53 / low HER2) cells (FIG. 1). . HCCR-1 expression levels were higher in BT-474 than in MCF-7.

Example  2: Immunohistochemical Analysis and Staining Analysis

In immunohistochemistry experiments, paraffin sections (5 μm thick) of human normal breast tissue and breast cancer tissue were used. The sections were incubated for 2 hours with affinity purified polyclonal anti-HCCR-1 antibody. Aminoethyl carbosol (AEC) was used as the pigment source. After immunostaining, sections were counterstained with hematoxylin. Pathologists counted at least 500 tumor cells in the areas most strongly stained for ER, PR and p53. Positive staining for ER, PR and p53 was defined by nuclear staining. According to the most accepted cutoff value, 10% positive staining of tumor cells was adopted as a positive result for ER, PR and p53. HER2 immunochemical staining results were defined according to staining criteria. Positive staining for HER2 was defined by membrane staining. Protoplast staining was not considered positive. Tumor cells with no immunoreactive (Score 0) or incomplete or faint membrane staining (Score 1+) were considered negative. HER2 was defined as positive if overall mild to moderate membrane staining (weak positive; score 2+) or overall strong membrane staining (strong positive; score 3+) was observed in 10% or more tumor cells.

The results of measuring the level of HCCR-1 expression in fresh 104 primary breast cancer tissues and their normal tissues are summarized in Table 1 and FIG. 2 below. Increased HCCR-1 expression levels in breast cancer tissues with (ER + / PR + / mutant p53 / high HER2), (ER + / PR + / wild p53 / intermediate HER2), and (ER + / PR + / wild p53 / low HER2) Was observed. On the other hand, HCCR-1 was not detected in breast cancer tissues with (ER- / PR- / p53- / low HER2) (Table 1 and FIG. 1A; bottom panel). These results show that HCCR-1 expression is highly correlated with known breast cancer prognostic markers.

Since HER2 overexpression / amplification has important consequences in the prognosis and treatment of breast cancer, its presence must be accurately measured (Bacus SS et al., Supra; Borresen-Dale AL, supra; Colditz GA et al., Supra and Slamon). DJ et al., Supra). However, several clinical methods of detecting HER2 are not complete in prognosis and prediction of response to trastuzumab (14, 26-28). HER2 test methods are still under development, and many clinical laboratories now use both IHC and FISH tests. An efficient test strategy is to perform FISH on tumors with 2+ staining intensity after immunostaining. This approach can minimize the risk of treating a patient who does not or is unlikely to treat a patient that is effective in trastuzimab; This is a critically important difference as it moves to the adjuvant setting with the use of a trajectory map (Hudis CA et al., Supra). The reported adjuvant trials used central laboratory reviews because of differences in interpretation between individual laboratories (Perez EA et al., J Clin Oncol 2007, 25: 118-145 and Santinelli A et al., Anal Quant Cytol Histol 2002, 24: 54-62).

The data indicate that HCCR-1 expression is closely related to HER2 activity in breast cancer tissues. This means that breast cancer prognosis is improved when combining the measurement of HCCR-1 levels and HER2 activity.

1 is a result of Northern analysis of HCCR-1 in human breast tissue and cell lines to determine the expression and pattern of HCCR-1 in breast cancer. HCCR-1 mRNA expression was compared in breast cancer cell lines (BT-474, MCF-7 and MDA-MB-231), fresh primary breast cancer tissues (C) and their corresponding normal counterparts (N). Human beta actin cDNA was used as control probe (bottom panel).

Figure 2 is a photograph of immunohistochemical staining to determine the correlation between HCCR-1 expression level and known breast cancer prognostic parameters (ER, PR, HER2, p53). Immunohistochemical staining for ER, PR, HER2, p53 and HCCR-1 expression in fresh frozen tissue derived from human breast cancer. All breast cancer tissues were derived from pathologically proven invasive ductal carcinoma. The nuclei of carcinoma cells show positive immunostaining for HCCR-1 in ER, PR, and p53 and plasma (top panel). HER2 immunohistochemical staining shows completely strong membrane staining (3+) of carcinoma cells (top panel). Negative immunostaining for ER, PR, p53, HER2 and HCCR-1 in breast carcinoma (bottom panel). Original enlarged, × 100.

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Claims (9)

Human cervical cancer oncogene (HCCR-1) from a patient's sample to provide information necessary for predicting the prognosis of estrogen receptor positive, progesterone receptor positive, p53 tumor suppressor gene mutations, and human epidermal growth factor receptor-2 (HER2) positive breast cancer As a method for detecting the expression level of HCCR-1, the expression level of HCCR-1 is selected for screening patients with HCCR-1 overexpression as estrogen receptor positive, progesterone receptor positive, p53 tumor suppressor gene mutation and HER2 positive. How to detect. The method for detecting the expression level of HCCR-1 according to claim 1, wherein the expression level of HCCR-1 is detected by detecting the expression of HCCR-1 mRNA. The method for detecting the expression level of HCCR-1 according to claim 1, wherein the expression level of HCCR-1 is detected using an antibody that specifically binds to the HCCR-1 protein. 4. The method of claim 1, wherein the prognostic prediction of HER2 positive breast cancer comprises determining whether to use a HER2 positive breast cancer specific therapy. 5. . The method for detecting HCCR-1 expression according to any one of claims 1 to 3, wherein the HER2 positive breast cancer specific therapy is administration or chemotherapy of an inhibitor of HER2 expression or an inhibitor of HER2 action. Way. Estrogen receptor positive, progesterone receptor positive, p53 tumor suppressor gene mutation and HER2 positive comprising a antibody that specifically binds HCCR-1 protein. Estrogen receptor positive, progesterone receptor positive, p53 tumor suppressor gene mutation and HER2 positive comprising a oligonucleotide that specifically hybridizes to HCCR-1 mRNA. A kit for predicting prognosis of breast cancer that is estrogen receptor positive, progesterone receptor positive, p53 tumor suppressor gene mutation and HER2 positive, comprising an antibody that specifically binds HCCR-1 protein and a binding detection means. A kit for predicting prognosis of breast cancer that is estrogen receptor positive, progesterone receptor positive, p53 tumor suppressor gene mutation and HER2 positive, including oligonucleotides that hybridize specifically to HCCR-1 mRNA and hybridization detection means.

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