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BRCA 1 AND BRCA 2 Gene Mutations and Increased
Risk Of Breast Cancer
Obed K. Agyei and Natalie A. Rich
Department of Biology, North Carolina State University
Abstract
Breast Cancer affects nearly 273,000 people every year in the United States, and
women account for almost 95% of the individuals affected. Private companies and
the U.S. government spend almost $1 billion on breast cancer research annually to
improve its diagnosis and treatment. Breast cancer is a complex, deadly disease
highly associated with genetic abnormalities. Since there are numerous types and
sub-types of breast cancer, it is very difficult to understand the basic cause of the
disease. The objective of this paper is to review how genetic abnormalities correlate
with different types of breast cancer. Research in this field has led scientists to
determine the main types of breast cancer that manifest in humans and the genetic
causes that lead to these manifestations. Much of the research in this field involves
experimentation with genes. BRCA1/2 genes were examined among patients with
breast cancer and those without the disease. DNA analysis of BRCA1/2 genes was
performed. Majority of the patients had mutations on the BRCA1/2 genes while the
other control group showed no sign of genetic mutations. Mutations of the BRCA1/2
genes are typically hereditary, but other factors such as radiation can trigger
mutations. Types of breast cancer are associated with the part of the breast whose
cells are being transformed due to mutated genes, either being the ducts, lobules etc.
Further elucidation of the affects of mutated BRCA1/2 is essential for understanding
human breast cancer manifestations and future treatment of this complex disease.
Conclusion
The amount of protein levels and gene mutations can determine a patient’s rick of
developing breast cancer and chances of survival. As it can be inferred from Figure
1, low levels of nm-23 (a specific type of protein) can reduce the survival rate of
infiltrating ductal carcinoma. These findings by Barnes were supported by three
pathologists who had similar conclusions. They concluded that high levels of nm-23
protein will increase a patient’s survival of infiltrating ductal carcinoma. Since
infiltrating ductal carcinoma is the most common type of all breast cancer, this
research is very significant because a progress can be made to reduce its popularity.
Few steps that could be taken to reduce the popularity of infiltrating ductal carcinoma
include developing medicines that have high concentrations of nm-23 protein. In
comparison to BRCA genes, similar conclusions could be drawn because a mutation
in BRCA 1 or BRCA 2 gene, as seen in Figure 2, will reduce the production of protein
by the BRCA genes. A reduction in protein production cannot prevent cells from
stopping its mass division which ultimately ends up in the build up of tumors. In
conclusion, BRCA 1 / 2 genes are highly associated with an individual’s risk of
developing breast cancer. Mutation of these genes reduces cell signaling
during cell division, thus increasing uncontrollable cell division in the body.
High level of nm23
Low level of nm23
Research Proposal
Figure 1 represent the survival rate of patients with low and high
nm-23 proteins.(Barnes et al 1991).
Introduction
Studies have shown that mutations in certain genes can lead a person to be more
susceptible to developing breast cancer. The most commonly studied genes are the
BRCA1 and BRCA2 genes. BRCA 1 and BRCA 2 are human tumor suppressor
genes that produces proteins to prevent uncontrollable cell growth. In the absence of
BRCA genes, the human body risk the chance of preventing mass cell division. The
purpose of this study is to review the risk of BRCA mutations, in comparison to other
factors such as protein levels, diet, health, and weight that may contribute to the
cause or prevention of breast cancer and the type of breast cancer associated.
Figure 2 illustrates breast cancer risk in women. Gray
column show risk in women with a strong family history of
breast cancer estimated by Easton et.al. (1995); Gray
stripped column shows risk in women carrying BRCA 1 or
BRCA 2 gene mutation estimated by Struewing et al.(1997);
White column shows risk in general population.
(Hofmann et al 2000).
As seen in Figure 1 and 2, breast cancer incidence rate is higher in Caucasians
women but however, more African-American women tend to die from breast cancer
than any other ethnic group. This disturbing findings cautioned us to design an
experiment that was geared toward examining the cause of this high mortality rate.
Goal 1: to determine the rate of BRCA1 and BRCA 2 gene mutations based on a
patient’s ethnicity and age.
Goal 2: Use Needle Breast Tissue Biopsy to extract cancerous tissues from a total of
20-30 breast cancer patients. Cells from six healthy patients will also be collected.
*Black
*White
Goal 3: Use siRNA gene slicing technology to temporary knockdown each of the
BRCA genes from the T47D cell lines to determine its effect on mutation rates.
General Goal Statement
Goal 4: Consult a geneticist to assist in the permanent removal of both the BRCA 1
and BRCA 2 genes from the breast cancer cell lines.
Mutations of the BRCA 1&2 tumor suppressor genes have a tremendous effect of the
type of breast cancer that an individual can develop, depending on the cell tissues
where the BRCA 1&2 genes are being mutated.
We expect to find a decrease in mutation rate when BRCA genes are permanently
deactivated. A deactivated BRCA gene will prevent all necessary mutations in the
TD47 cancer cell lines.
Materials and Methods
We expect to find significant differences in BRCA 1 and BRCA 2 mutation rate
among African American and Caucasian women.
Gene Expression Profiling:
[To accurately determine the state of cancerous tumors.]
• A set of human DCIS and invasive mammary tumors were analyzed using gene expression
profiling.
• Gene Expression of TP53 genes were examined in normal breast epithelial cells and mutated
breast epithelial cells.
•A test was conducted on somatic cells affected by cancerous genes to identify their phenotypes.
•DNA analysis of the BRCA1 and BRCA2 genes was performed over the course of ten years on
women from various ethnic groups.
•A genetic test was conducted in mice with one or more mutated genes.
•DNA and RNA were extracted from frozen samples of invasive carcinoma tissues and analyzed
for genomic expressions.
Population Study
•Families with the BRCA1 and BRCA2 mutations were investigated to determine the risks of
developing breast cancer
•A database of patients with early stages of breast cancer were studied to determine the status
of the TP53 tumor suppressor gene.
•A nationwide study was conducted to help determine non-genetic factors for developing breast
cancer in premenopausal and postmenopausal women.
Protein Level Analysis
•Infiltrating ductal carcinoma were collected from the University of Jacksonville to be accessed
for protein staining patterns.
•Medullary carcinomas of the breast were obtained and examined for the presence of cytokeratin
Figure 3. A representation of female breast cancer
incidence rates in the U.S with respect to ethnicity. (CDC)
Figure 4. Shows female breast cancer mortality
rates in the U.S with respect to ethnicity. (CDC)
*(Center for Disease Control and Prevention, 2011). Rates per 100,000 persons among 19 age groups.
Results
•Infiltrating ductal carcinomas with low nm-23 protein had a low rate of survival.
•Human Ductal Carcinoma In-Situ genes express markers similar to invasive ductal carcinomas in
mice.
•Invasive ductal carcinomas and medullary carcinomas are positive for Cytokeratin 5 and 6 proteins
•Infiltrating Lobular Carcinoma is positive for 92.7% of estrogen and has a higher presence of p53
tumor suppressor gene
•Examination of Inflammatory breast cancer tissues showed that the genes had recurrent
amplifications than the genes in non-inflammatory breast cancer tissues
•BRCA1/2 mutations are commonly found in breast cancer patients.
•Mutations in the BRCA1/2 genes are found in people with a family history of breast cancer.
•BRCA1/2 gene mutations increase the rate of tumor growth in patients with breast cancer.
•BRCA1/2 genes increase the risk of a person developing breast cancer by 85%.
•Majority of BRCA ½ gene mutations are found in ancestral groups
Acknowledgements
This work was supported by the College of Agriculture and Life Sciences , Department of
Biology at North Carolina State University, Dr. Miriam Ferzli and Elizabeth Overman.
References
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