1.0 Introduction to Breast Cancer
Genetic diseases are widespread. Cancer is a genetic disease and is a major cause of death. Cancer is caused by mutations within the genome that result in the development of oncogenes or tumour suppressor genes which both cause the uncontrolled proliferation of cells in opposed ways. The oncogenes are mutated genes that in their pre-mutated state, promote cell replication. However, due to the mutation, these oncogenes cause either enhanced expression or altered nature of protein products. Tumour suppressor genes (‘TSG’) are mutant genes that normally restrain cell growth. It is the most common cause of death for women with statistics showing one in 13 Australian women who live to the age of 74 will be diagnosed with it sometime during their lifetime.
This dissertation will discuss the nature of breast cancer, the factors causing breast cancer with an emphasis on familial inheritance, methods for testing for breast cancer and available treatments. The prevalence of breast cancer and the high mortality rate especially for women above the age of 70 signifies a need for increased awareness in the community both for prevention and support for those affected by this destructive disease.
2.0 What is Breast Cancer?
Cells make up many different parts of the body – skin, bones, brain, heart, and breasts. These cells are replaced when they become old or injured by replication at varying rates depending on the part of the body. The replication process is regulated by genes that code for proteins which increases or decreases the rate of division. These genes are proto-oncogenes (when mutated become oncogenes) and TSG’s. The abnormal genetic material translates into non-functional products which causes the cells to multiply without restraint. Most breast cancers are caused by a mutant inactivitation of TSG. In breast cancer, the proliferated cells form a hard mass of cancer that can sometimes be felt upon self examination. The proliferated cells can detach from the tumour and invade other tissue in a process called metastasis.1 This process changes the tumour from being classified as benign to malignant increasing the threat to the life of the person. Malignancy is a great threat as such cancerous cells can migrate throughout the body and to vital organs such as the brain or the lungs thus deleteriously altering their functional capacity.
To understand where these proliferated cells can form within the breast, the anatomy of the breast will be discussed. The breast’s main function is to supply a newborn baby with milk via the mammary glands made up of glandular units. These units are joined by ligaments and fatty adipose tissue. The breast is a sexual organ controlled mainly by hormones released from the pituitary gland and the ovaries. During the menstrual cycle, the hormones progesterone and oestrogen cause changes to the breast. The underlying muscles consist of the pectoralis major, pectoralis minor, serratus anterior and the latissimus dorsi. A diagram of the breast can be seen in figure 2.1.
(insert diagram from pg 7 breast cancer nursing)
Breast cancer mainly occurs in the epithelial lining of the terminal duct lobular unit. These cancers are termed adenocarcinomas. Depending upon the size and aggressiveness of the tumour, the tissues within and the muscles surrounding the breast can all be affected.
Although breast cancer in men does occur, it is uncommon with only 0.8% of breast cancers affecting males. The rarity of the illness does not detract from its physical severity or psychological effects. The affected male would need the same care as a woman as well as an understanding of the unique situation as a man with the disease.
3.0 Causes of Breast Cancer
Breast cancer is caused by a combination of factors that cause mutation in the DNA. These mutations can be inherited, due to the environment or both. These factors will be discussed individually as follows.
3.1 Environment
The lifestyle of a person, their diet, the chemicals around them, and their reproductive natures are factors which contribute to whether or not such person is susceptible to the development of breast cancer. Knudson’s ‘Two Hit Hypothesis’ states that for cancer to develop, there needs to be mutations in both functional copies of TSG in a cell. If a mutated allele was inherited, the second allele would have to be mutated due to environmental factors for cancer to develop. Thus both functional copies of the gene are altered.1 Some environmental factors that may cause the mutation both or the second allele in a cell will be discussed.
3.1.1 Mutagens
There are several substances that are known to increase the risk of cancer whether by exerting carcinogenic effects indirectly or acting directly as a carcinogen. Alcohol is such a substance that is known to exert toxic effects on the liver. However, it can also exert a carcinogenic effect indirectly to the breast by cell stimulations. The breasts being affected by hormonal stimulus, especially during the menstrual cycle, can also be affected by hormone replacement therapy after menopause. Studies have shows the risk of cancer was even higher in women who used a combined oestrogen and progesterone therapy. There has been significant evidence of women development breast cancer after they have been treated with radiotherapy and chemotherapy for Hodgkin disease. This is especially significant with those who were treated for Hodgkin at a very young age. This is similar to the breast cancer caused by exposure to the radiation from atomic bombs. The aromatic hydrocarbons in cigarette smoke is carcinogenic not only causing lung cancer but also other cancers such as breast cancer. The effect of smoking acts in a similar way as the poly-cyclic hydrocarbons in well done meat which is also carcinogenic.6 A correlation was shown between a diet high in animal fat and high fat dairy products in pre-menopausal women causing an increase in the risk of breast cancer. Therefore, exposure to substances such as such as alcohol, tobacco, hormone replacement therapy, high fat diet, chemotherapy and radiotherapy may lead to an increased risk of breast cancer.
3.1.2 Reproductive Factors
There are several reproductive factors that show a correlation with breast cancer. There is a decreased risk with later menarche, early menopause, early pregnancy and lactation.8 Some tests have shown that early pregnancy protects against breast cancer because it spurs a tumour suppressor protein called p53.
3.1.3 Other Environmental Factors
Breast cancer is more common is western countries. However, when Asian women migrate to the west, their grandchildren experience similar levels of breast cancer as that of the local population of the host country. Therefore, the environmental component is a significant contributor to breast cancer. Regular exercise decreases the risk of breast cancer as is a lower distribution of body fat.
3.2 Familial Inheritance
Less that 10% of all breast cancer is inherited. However, there has been extensive research on inherited breast cancer. A summary of such information is set out below.
3.2.1 Familial Aggregation
The hereditary forms of breast cancer are generally more aggressive that the more common acquired forms of the disease. A family history of breast cancer increases the risk for the disease. This risk is even greater if the woman has a first-degree relative diagnosed with breast cancer at a young age or if there are more than one first-degree relative with the disease. This clustering of breast cancer is known as familial aggregation. This aggregation indicates a strong fundamental risk factor that is shared amongst the relatives. The reason for familial aggregation of breast cancer is still limited and is the subject of continuing research. Lifestyle and environmental risk factors only explain a small amount of familial aggregation.
It is considered that genetic risk factors may well explain the majority of familial aggregation. Mutations in the BRCA1 and BRCA2 genes are linked with greater breast cancer risks of 10-fold or more. However, they only explain a small portion of familial aggregation. The familial and genetic aspects of susceptibility for breast cancer include more genes than BRCA1 and BRCA2. This is especially so for disease in women diagnosed when younger than 40 years. It has been found that approximately 5%-10% of breast cancers diagnosed in women younger than 40 years may be due to mutations in these genes.
3.2.2 BRCA1 and BRCA2 Susceptibility Genes
There are two most commonly identified breast cancer susceptibility genes, BRCA1 and BRCA2. BRCA1 is located at 17q21 whilst BRCA2 is located at 13q12-13.9 These genes are TSG’s and, as explained in section 1.0, usually restrain cell growth. They have also been described as ‘caretaker genes’ and ensure the genetic integrity is not compromised through loss, duplication or rearrangement of chromosomal DNA. BRCA1 coded protein repairs DNA breaks and induces cell cycle arrest at the G1/S, S and G2/M checkpoints. See figure 3.2.1. However, the exact mechanism of the inactivation of how BRCA1 leads to malignant cancer is unknown.
A study showed that mutations in BRCA2 leads to chromosomal instability due to flaws in the repair of double-strand DNA breaks by homologous recombination. , The exact mechanism of this process is also unclear. However, it is known that these breast cancer susceptibility genes are large and code many different proteins. Therefore, these mutant genes carry a much higher risk of breast cancer – approximately 50 to 85 percent.
3.2.3 Dominant Inheritance
The mutated BRCA1 and BRCA2 susceptibility genes are a dominantly inherited through either the maternal or paternal gene line. This means that only one mutated allele is needed with a normal allele for the phenotype to be observed. This results in a loss of function mutation in the BRCA1. There is a variation between women in penetrance of the mutation. Women who inherit a mutated BRCA1 gene have a 3 in 5 chance or 60% chance of developing breast cancer before the age of 50. However, the other BRCA1 allele needs to be lost as well for malignant breast cancer to develop. This is due to environmental sources of mutations. This is in keeping with Knudson’s Two Hit Hypothesis as discussed above.
4.0 Testing Procedures
There are several ways that breast cancer the risk of can be detected. The following sections briefly canvass some of these methods.
4.1 Genetic Testing
There are availabilities of genetic testing for BRCA1 mutations. However, this gene is very large with more than 600 different mutations having been identified. 95% of these mutations result in truncation of the BRCA1 protein mainly due to ‘frameshift’ and ‘nonsense’ abnormalities. The risk of cancer for an individual varies between families because of the different mutations and the effect of polymorphisms (different versions of an allele). These can include polymorphisms in the androgen receptor, the steroid-hormone receptor coactivator NCOA3 and the androgen receptor gene.
Due to the large amount of mutations that can occur in BRCA1, the genetic screening process is expensive. It is suggested that the screening methods available can only detect 60-70% of BRCA1 mutations because DNA sequencing can miss mutations that alter BRCA1 protein stability or expression and might also be unable to distinguish complete loss of single allele as a result of large deletions.
Less than 50% of individuals in high risk families ask to be screened. Some reasons given included perceived cost of testing, perceived inaccuracy of tests, insurance difficulties and negative psychological effects.
4.2 Mammography
Mammography is an X-ray technique that can be used to aid diagnosis and detect impalpable tumours of the breast. The breast is compressed between two plates and either a single view or a two view of the breast is taken.4 If the films produced shows some abnormalities, a range of other techniques may be utilized to further aid in diagnostic investigations such as clinical examination, ultrasound, fine need aspiration, sterotactic fine needle aspiration and trucut needle biopsy. The increased use of mammography in the 40-69 age bracket resulted in a 44% fall in breast cancer mortality. This highlights the importance of mammography within that age bracket.
5.0 Treatments
Surgery is often used for primary breast cancer to eradicate the primary tumour and the local area surrounding it in the hope of achieving control over the disease. There are two broad categories for surgery. Breast conserving surgery aims to remove the tumour just beyond the histological margin on all sides. This is only suitable for tumours that have clear margins and are unifocal. The size of the excision is dependant on the size of the tumour. The second broad category is the mastectomy where the breast is removed as well as underlying pectoral muscles. This method is used for those with ill-defined margins of the tumour, tumours that extend widely within the breast, directly involve the nipply or those who do not choose breast conservation.
Radiotherapy is commonly used after breast conserving surgery. This targets cells during mitosis. Cancers are constantly replicating and thus are more likely targets of the radiotherapy treatment. Radiotherapy after surgery reduces the chance of cancer reoccurrence.
Systemic adjuvant therapy includes hormonal manipulation and or cytotoxic chemotherapy. The aim of this mode of therapy is to treat undetectable cancer and improve survival. Chemotherapy side effects include nausea, vomiting, tiredness and alopecia (loss of hair). Other side effects can also include early menopause.
6.0 Conclusion
The mutations in the genome leading to breast cancer can be inherited (familial), caused by environmental factors or a combination of both. The most common method for testing for breast cancer is mammography. However, genetic testing is an emerging technique used to detect the likelihood of presenting breast cancer. The treatments available are usually prescribed in various combination depending on the stage and position of the breast cancer. These would include radiotherapy, chemotherapy and surgery and endocrine therapy.
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