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Breast tumor and/or biopsy molecular profile PDF Print E-mail
Thursday, 25 November 2010 15:54

PRECIOUS INFORMATION TOWARDS PROGNOSIS, THERAPY AND TUMOR MANAGEMENT

The transformation of normal cells to cancer cells is caused by the abnormal expression of several genes with important cellular functions. The rapid development of molecular sciences in recent years contributed to revealing the identity of many of these genes. Also demonstrated the role of these genes in the mechanism of development, behavior and response of cancer cells to treatment. A modern and accurate way to accessing the activity of these genes is through gene expression and molecular profiling of the tumor.

Determination of gene expression is conducted by the method of quantitative Real Time PCR (Figure 1). The more active is a gene, the more copies of its corresponding mRNA will be present in the isolated mRNAs tank. Conversely, the less active is a gene the fewer the copies of mRNA will be. By using unique primers and/or probes for each gene the number of copies of mRNA for each particular gene analyzed can be determined with great accuracy. By this way, we can be easily identify overactive and underactive genes for a certain tumor compared with the ones of a corresponding normal tissue. Thus, we can outline major mechanisms of tumor development and possible targets for personalized therapy.

 

The molecular profile of breast cancer tumor

For the production of a molecular profile of a breast tumor, the expression of certain genes is determined. Such genes are the ones coding for tyrosine kinase receptors (RPTKs),  (HER2, EGFR, ERBB3, MET), estrogen receptors (ESR1α, PgR), the chemokine receptor CXCR4 which is associated with the metastatic potential, the transcription factor HOXB13, the interleukin receptor IL17BR, the expression and simultaneously the detection of common mutations in tumor suppressor genes, (p53, PTEN) and the expression of the antiapoptotic genes BCL2 and SURVIVIN. By studying the expression of these genes we know the prognosis that will have the particular mammary tumor and in combination with a mitotic index gene signature (BUB1B, CENPA, NEK2, RACGAP1, RRM2) its risk. Furthermore, the expression of certain genes (ERCC1, BRCA1, RRM2, TYMS, IFIT3, BUB3, BAG1, MAPK14) is monitored to determine the response of cancer cells in common chemotherapeutic drugs (Figure 1).

 

The advantages of gene expression compared to immunohistochemical methods

It is scientifically accepted that gene expression and immunohistochemistry provide comparable results. However, a major advantage of gene expression in relation to the immunohistochemical methods is the small amount of sample required. Even a fine needle biopsy (FNA) can reveal the expression of dozens of genes, which is almost impossible with immunohistochemistry. Furthermore, the expression of the analyzed genes is measured accurately and quantitatively compared to other reporter genes whose expression is not altered in pathological conditions, in contrast to the immunohistochemistry where the occurrence and intensity of a color that indicates the expression of the corresponding protein is monitored. Moreover, by using gene expression analysis, common technical problems such as availability and functionality of certain antibodies used in immunohistochemistry are overcomed.

 

(A)

Molecular Volume and Profile Breast Biopsy

(B)

Molecular Volume and Profile Breast Biopsy

FIGURE 1:

(A) Real-time gene expression data of selected genes relative to the reference gene GAPDH. The closer to the Y-axis the curves are formed, the greater the expression of the respective genes. Increased expression is observed for the genes encoding the estrogen receptors ESR1, progesterone PGR and HER2. Also, the increased expression of the antiapoptotic gene BCL2 is associated with good response in treatment with endocrine agents. There is also relatively low expression of MET receptor associated with the invasive capacity of tumor cells, as well as the oncogene p53. The low ratio of gene expression HOXB13/IL17BR suggests absence of tumor aggressiveness, while the increased expression of genes that consist the mitotic indicator of development (BUB1B, CENPA, NEK2, RACGAP1, RRM2) has been associated with response to certain chemotherapies.
(B) Display of quantitative differences in gene expression (A).

 

CONCLUSIONS

Cancer cells molecular profile contributes substantially to personalized medicine. Even identical abnormal breast cancer cell types differ significantly in their molecular profile. Therefore, the information provided by the molecular profiles contributes significantly to the proper management of tumors by the treating physician. The contribution of these analyses is fundamental in predicting tumor progression and identification of targeted therapies, as well as response to various chemotherapeutic drugs. The later is an important advantage, because the majority of patients receiving chemotherapy do not respond.

 

Suggested bibliography

  1. Konigshoff et al. HER-2/neu gene copy number quantified by real‐time PCR: Comparison of gene amplification, heterozygosity, and immunohistochemical status in breast cancer tissue. Clinical Chemistry 2003; 49:219‐229
  2. Silvestrini et al. p53 and bcl2 expression correlates with clinical outcome in a series of node positive breast cancer patients. J Clin Oncol 1996, 14:1604-1610
  3. Maurice et al. HOXB13 to IL17BR Expression Ratio Is Related With Tumor Aggressiveness and Response to Tamoxifen of Recurrent Breast Cancer J Clin Oncol 2007, 25:662-668
  4. Ma et al. A five-gene molecular grade index and HOXB13:IL17BR are complementary prognostic factors in early stage breast cancer. Clin Cancer Res. 2008,14:2601-2608
  5. Schmidt et al. p53 expression and resistance against paclitaxel in patients with metastatic breast cancer. Cancer Res Clin Oncol. 2003, 129:295-302
  6. Pandolfi PP. Breast Cancer - Loss of PTEN Predicts Resistance to Treatment. N Engl J Med 2004; 351:2337-2338
  7. Staaf et al. Identification of Subtypes in Human Epidermal Growth Factor Receptor 2–Positive Breast Cancer Reveals a Gene Signature Prognostic of Outcome J Clin Oncol 2010, 1813-1820
  8. Cheang et al. Gene expression profiling of breast cancer. Annu Rev Pathol. 2008, 3:67-97.
  9. Wang et al. Elevated expression of ΕRBB3 confers paclitaxel resistance in erbB2-overexpressing breast cancer cells via upregulation of Survivin. Oncogene 2010; 29:4225-4236
  10. Ponzo et al. MET induces mammary tumors with diverse histologies and is associated with poor outcome and human basal breast cancer. PNAS 2009; 106:12903-12908
  11. Thuerigen et al. Gene Expression Signature Predicting Pathologic Complete Response With Gemcitabine, Epirubicin, and Docetaxel in Primary Breast Cancer. J Clin Oncol 2006; 24:1839-1845

 

 

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