Research Paper on "Genetic Pathway of Breast Cancer and Gene Therapy"

Research Paper 8 pages (2282 words) Sources: 5

[EXCERPT] . . . .

Genetic Pathway of Breast Cancer and Gene Therapy

A PROMISING LEAD TO A CURE

This study will discover new pathways in predicting the prognosis of breast cancer and the benefits, strategies and approaches of gene therapy. Findings will update current knowledge on the prognosis of breast cancer and therapeutic options, specifically gene therapy.

A Step Ahead in Breast Cancer Prognosis

The American Cancer Society reported that in 2009 alone, approximately 192,000 cases were diagnosed of breast cancer and of which 40,610 died (Ma & Kosorok, 2010). One in 8 women in the U.S. face the lifetime risk of developing invasive breast cancer and 1 in 33 face the risk of dying from it. Studies suggest that genomic measurements may predict the prognosis of breast cancer and form the basis for responsive therapy. Multiple gene profiling has been conducted in search for those genomic measurements and that prognosis. A new pathway analysis method was devised beyond all other existing alternatives to assess four breast cancer gene profiling studies. It focused on predictive power rather than estimation accuracy. It identified 96 pathways, many of which had strong biological basis and were considered markers in independent studies. The methodical steps in detecting pathways were the selection of multiple and comparable gene profiling data sets and their separate processing; matching measured genes in all studies; constructing known gene pathways with the use of public databases; computing a statistic and corresponding p-value, which can quality the predictive power of genes within specific pathways; pooling p-values computed from datasets using Fisher's method and computing for the overall significance level to obtain predictive power; and using the fake discovery rate approach and identifying pathways with significant predictive power (Ma & Kosorok).

This method has certain aspects superior to existing alternatives (Ma & Kosorok, 2010). It assesses predictive power of gene pathways while alternatives focus only on model fitting accuracy. It accounts for the joint effects of multiple genes in a pathway, while alternatives focus only the marginal gene effects. And it works on multiple heterogeneous data sets, while alternative methods take on only a single data set. This new method is a useful alternative to existing methods, which can lead to new and significant insights into breast cancer prognosis (Ma & Kosorok).

Multi-gene Predictors

Genome profiling has vastly enlarged the knowledge of genes and genetic pathways associated with the development and progression of breast cancer (Ross, 2008). Many commercialized multi-gene prognostic and predictive tests evolved as a consequence. Some platforms were immunohistochemistry, FISH, quantitative real-time PCR, and genomic microarrays and gene chips. Diagnostic kits and centralized commercial laboratory assays are now obtainable with the data analysis tools and algorithms for calculating test results (Ross). The assays, however, have yet to be fully evaluated and proven effective in a large number of clinical trials. As such, they have caused apprehensions among clinicians and healthcare economists. The scientific validity, true use and cost-benefit ratios of the assays continue to be questioned. In the meantime, they tend to be mis-used, such as using the test in wrong clinical settings and producing misleading reassuring results. Required clinical trials, such as the TAILORx and the MINDACT trials in the U.S.A. And Europe, are currently being undertaken, questions will remain un-answered for many years (Ross).

MicroRNAs Predict Status in Breast Cancer

Receptors of phenotypically diverse tumors in breast cancer have been shown to change while the disease progresses and in response to therapy (Lowery et al., 2009). These are estrogen, progesterone and HER2/neu receptors. Micro-RNAs are involved in diverse biological processes, especially in many neoplasms. In breast cancer, these micro-RNAs function as regulators of tumor behavior and progression. An expression profiling of 453 miRNAs was conducted on 29 early-stage breast cancer specimens, using artificial neural networks or ANN. ANN identified predictive miRNA signatures, which corresponded with estrogen, progesterone and HER2/neu in specific breast cancer phenotypes. Decreased expression of miR-342 in triple-negative breast tumors, increased miR-342 in luminal B. tumors, and down-regulated miR-520g in ER and PR-positive tumors indicated poorer prognosis for breast cancer. This discovery of genetic regulation will improve current understanding of molecular targets and in identifying pathways in predicting response and resistance to therapy. Moreover, it will be part of an optimal approach to better breast cancer therapy (Lowery et al.).

Gene Therapy

Cancer gene therapy is the deliver of genes to cancer cells in the body (Abaab & Criss, 2002). The goal is for these delivered genes to enter the cancers to directly or indirectly produce therapeutic effect on the person. Delivery requires the use of carriers, called vectors, in targeting cancer cells. For best effects, the vector and the genes must be stringently screened. They must have high transfection efficiency; must target the specific tumor cells, including metastatic cells; and must be controllable cells combined with apt promoterenhancer sequences. Vectors are viral or non-viral. Viral vectors are more often used than non-viral because of their higher transfection efficiency. The most commonly used are retroviruses for all diseases, including cancer, taken from Moloney murine leukemia virus. Adenoviruses are also commonly used although they produce immunological and inflammatory reactions, which discourage repeat administrations. These vectors are currently undergoing improvement. Combining the advantages of retroviruses and adenoviruses are also currently being attempted through a chimeric virus (Abaab & Criss).

The authors list the strategies as the delivery of suicide genes, the delivery of tumor suppression genes, inhibition of angiogenesis, immunotherapy, the use of oncolytic viruses, and ribozyme or antisense targeting (Abaab & Criss, 2002). The two major strategies in targeting vectors to metastatic or non-metastatic cancer are vector targeting and transcriptional targeting. Vector targeting is sub-divided into physical targeting and biological targeting. Physical targeting applies to the route of application, like intra-cancer tissue. Physical targeting is used in almost all vector applications at present. It is in the application of biological targeting that some problems present themselves. Transcriptional targeting addresses the level of gene expression. This, in turn, can be controlled by appropriate promoter/enhancer elements pertaining to the targeted cells (Abaan & Criss).

The appropriate approaches and strategies in gene therapy have developed faster than the appropriate vectors (Abaan & Criss, 2002). At this time, viral vectors have shown to produce the best mechanism in gene delivery. New viral vectors keep surfacing to add to existing ones. It is not commonly known that adenoviral vectors are much more used than retroviral vectors. Retroviral vectors are used when the disease required gene correction rather than destruction. Every therapeutic strategy has been successfully tried in breast cancer experiments. Hence, they are continuously upgraded and optimized for therapy purposes in breast cancer. There have also been reports that gene therapy can be used in combination with other therapies. The delivery of exogenous tumor suppressor genes can be combined with chemotherapy or radiotherapy. The combination has shown to reduce drug resistance and toxic side effects of chemotherapy. Immunotherapy and the delivery of suicide genes can be or have also been used as part of a combination (Abaan & Criss).

Gene therapy appeals because it enables the targeting of all cancer cells in order to destroy them (Abaan & Criss, 2002). It also allows the delivered gene vectors to remain in blood circulation and continue seek out cancer cells at a limited period of time. One projection is a treatment with a special gene vector, carrying a special gene, aimed at a specific cancer. Other current advances can likewise produce new and specific types of cancer vaccines and therapies in the foreseeable future (Abaan & Criss).

Genetic Basis for Breast Carcinoma and Gene Therapy

Cancer develops as a multi-step process and characterized by genetic alterations (Stoff-Khalili et al., 2006). These alterations influence the main cellular pathways in cancer growth and development. Most experts agree that these alterations are chromosomal alterations or loss of tumor suppressor function and the amplification of oncogenes. The most common type of somatic alteration in human breast tumors is the loss of heterozygosity. This is the loss of one allele in a patient's tumor for which the normal cellular DNA marker is heterozygous. It is significant if it occurs at the locus of tumor suppressor gene and there is inactivating mutation in the second allele. This loss has been found in chromosomes, such as 1, 2, 4-11, 13, 16-18, 22 and X 6-9. It corresponds to loss or inactivation of TSG cells. TSG cells' loss of function induces malignancy. These cells are usually viewed as negative regulators of growth or other functions, which enhance invasive and metastatic protential. Sometimes, TSGs do not mutate but some other mechanism may inhibit its expression or function. Inhibiting mechanisms include methylation of the gene promoter, which suppresses its transcription; faster rate of proteasonal degradation; or abnormalities in other proteins, which interact with the gene product (Stoff-Khalili et al.).

Gene Therapy Approaches

These are mutation compensation, molecular chemotherapy, proapoptotic gene therapy, antiangiogenic gene therapy, genetic immupotentiation, and genetic modulation of resistance or sensitivity (Stoff-Khalili et al., 2006).

The authors trace the beginnings of mutation compensation to the theory… READ MORE

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