The Role Of Genetics In Breast Cancer Biology Essay

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Breast cancer accounts for 16% of all cancers in the UK. 1 in 8 woman will develop it but it is still unknown exactly what causes it. There are particular risk factors that we know about though. One of these is if your family has a history of breast cancer related incidents. This would then suggest that some forms of breast cancer are related to our genetic code. Genes are passed on from our parents and if these are faulty (gene mutations) then there could be a greater chance of developing breast cancer. Hereditary gene mutation accounts for roughly 5% of all breast cancer cases. There are several genes that can be held accountable for this. Some of these are TP53, PTEN, STK11/LKB1, CDH1, CHEK2, ATM genes. The big 2 are BRCA1 and BRCA2 (Breast Cancer 1 & 2) they are responsible for more instances of breast cancer than the others. With the knowledge of these gene mutations comes some very innovative ways of testing for them. In this report we are going to look at the main genes responsible for the development of breast cancer. We will touch on how they perform when there is no mutation and how mutations relate to breast cancer. Somatic and hereditary mutations will also be explained and compaired. Last of all the process of risk reduction will be explained which will include genetic screening and lifestyle choices.


TP53 is the gene that is responsible for the code which is needed to synthesise the protein known as the "tumour protein p53". The protein is found in the nucleus of the cell and is bound to the DNA. When working correctly the protein regulates cell division so that tumours don't form. It also has another very important role. Let's say for instance that the cells have been exposed to radiation or burns to the extent that DNA has been damaged. The protein has the very important role of deciding whether the DNA can be repaired or whether the cell has to go through the process of apoptosis (programmed cell death). This example alone shows the importance of this gene working correctly so that transcription works correctly to produce the proper protein and so begs the question "How does this relate to breast cancer?" Well there are a few answers to that question. One result of a defective TP53 gene is Li-Fraumeni syndrome. Any cell that has this type of defective TP53 gene has a far greater risk of contracting cancer "Individuals with LFS have up to a 50% chance of developing cancer by age 40 and a 90% chance to develop cancer by age 60. Breast cancer appears to be the greatest risk for women. However, less than 1% of all breast cancer is thought to be related to LFS." [1] Another cause of breast cancer by a defective TP53 gene is caused by the somatic mutations which account for "20% to 30% of all breast cancer cases" [2] . The usual cause is that an abnormal amino acid is produced in the protein chain which makes the protein ineffective and therefore causes the cell to grow and divide erratically. The same symptoms can be noticed if the TP53 gene is absent in a cell.

TP53 gene location on the chromosome


Phosphatase and tensin homolog (PTEN) is a very important gene that produces a protein found in nearly all tissue. The PTEN protein is an enzyme that modifies fats and other proteins by removing phosphate groups. When working correctly the enzyme, created by the PTEN gene, is involved in the chemical pathway which signals apoptosis (programmed cell death). PTEN is also thought to help in the control of cell adhesion, cell migration and angiogenesis. Once again the question of how this gene relates to breast cancer. All of the roles of the enzyme created by this gene add up to a key tumour suppressor as all are involved in cell proliferation in some way. The main cancerous danger of this gene is caused by somatic mutations that change the gene, this results in a defective enzyme being produced. This defective enzyme is not able to control cell proliferation as it should and therefore cancerous cells can be allowed to reproduce and grow at an uncontrollable rate.

PTEN gene location on the chromosome


Serine/threonine kinase 11 (STK11) gene creates a protein that acts as a tumour suppressor. The enzyme stops the cell from reproducing irregularly and is also another link in the promotion of the process known as apoptosis (programmed cell death). Another useful role by this enzyme when the gene is working correctly is the polarisation effects it has on cells e.g. it assists in the orientation of cells in tissue. The protein also controls how much energy is used by the cell. All these are key control elements in tumour suppression. Mutations in this gene cause Peutz-Jeghers syndrome. Over 140 different mutations [3] of the STK11 gene have been reported to cause this syndrome. Mutations usually create a shorter non-functioning version of the enzyme and studies show that when the enzyme isn't functioning properly the cell divides to quickly and polyps are formed which sometimes develop into cancerous tumours. With the defective enzyme comes as a far larger risk of breast cancer. Only a small percentage of breast cancers are actually related to Peutz-Jeghers syndrome which are usually inherited. It's even rarer for breast cancer to be caused by somatic mutations in this gene but it has happened. Cells tend to uncontrollably divide which in turn leads to malignant growths.

STK11 gene location on the chromosome


Cadherin 1, E-cadherin (epithelial) (CDH1) is responsible for the production of the protein E-cadherin. Cadherin's are proteins that bind cells together (cell adhesion) to form tissues. They are calcium dependent which means they require the presence of calcium to perform properly. In addition to cell adhesion E-cadherin's have some very important roles which include the transmition of chemical messengers from cell to cell, control of cell movement and control of selected genetic behaviour. Studies suggest that CDH1 is a tumour suppressor gene which helps regulate cell proliferation and stop cancerous tumours from growing. Also because cadherin's help cells stick together it is thought that they stop cancerous cells from breaking free and entering the blood stream which limits the spread of cancer to other tissues (metastasising). There is an increased risk of breast cancer when the CDH1 gene is mutated. Inherited mutations of the CDH1 gene increase the risk of lobular breast cancer that begins in the mammary glands. Somatic mutations of this gene are common but so are damages to the DNA that calls upon the gene. It is thought that the genetic mutations lead to uncontrollable division and growth of the cells. Also the lack of E-cadherin's, through errors in its synthesis, can lead to cancerous cells metastasising to other parts of the body.

CDH1 gene location on the chromosome


Checkpoint kinase 2 (CHECK2) is the gene responsible for the synthesis of the protein checkpoint kinase 2. The protein itself acts as a tumour suppressor. This means that it controls the cells proliferation. The protein becomes active when DNA becomes damaged in the cell. Cell division is then halted and CHEK2 then interacts with other proteins such PT53 to see if the DNA can be repaired or if the cell should be destroyed through the process of apoptosis. Damages can easily happen through exposure to things such as toxic chemicals, UV rays from the sunlight, radiation burns etc. Another way that DNA can break is through the daily genetic processes that get carried out. Mutations in this gene slightly increase the risk of breast cancer. The most known dangerous mutation is the deletion of a nucleotide at the position 1100 in the CHEK2 gene. This creates a shortened version of the protein that is ineffective in its tumour suppressor role. Cells are allowed to divide and grow uncontrollably which can then lead to cancerous tumours in the breasts. There are also links to Li-Fraumeni syndrome from mutations of this gene but it is known whether this gene is a cause or a result of the syndrome.

CHEK2 gene location on chromosome


Ataxia telangiectasia mutated (ATM) is a very interesting gene. It is responsible for the synthesis of a protein that is located in the nucleus of cells. Its primary role is to control the growth and division of cells but it also plays a large role in the growth of the nervous system and the immune system. The ATM protein plays a main role in DNA damage recognition and repair. It activates the enzyme required to fix the broken strands. These strands can become broken through daily tasks such as cell division where the information in the DNA is called upon. Other damages to be repaired may once again result from external sources like radiation, damage from UV rays and burns. In relation to breast cancer there seems to be three forms of instances when it comes to ATM. The first is the mutation of one of the genes in each cell. This creates an ineffective protein that hinders the performance of the control of cell proliferation and DNA repair which in return leads to cancerous tumours. The second instance is the deletion of the gene which mean the cells only hold one copy of the gene which therefore means that only half the amount of the required protein is synthesised. This leads to an ineffective control of cell proliferation and DNA repair which in turn can also lead to a higher risk in breast cancer. In the third instance both ATM genes in the cell have mutated and they form a short ineffective protein that does not function properly. This is known as ataxia-telangiectasia. When the ATM protein is not working the cell becomes very sensitised towards radiation and things like UV rays. Other genes in the cell become damaged and mutated as a result of the missing protein and this can lead to cancerous tumours.

ATM gene location on the chromosome

The ATM gene is located on the long (q) arm of chromosome 11 between positions 22 and 23.


MutL homolog 1 (MLH1) is a gene that produces a remarkable protein involved in the repair of DNA. The gene belongs to a group called the mismatch repair genes. Basically the protein created by this gene is an essential part in the process that corrects wrongly produced DNA strands. If a DNA strand is created during DNA replication and a part of it has the wrong code then this protein, paired with the PMS2 protein, removes the wrongly created part and replaces it with the correct order of bases. Mutations in this gene can cause a disorder known as Lynch syndrome. When these genes are mutated an effective protein is produced which leads to a build-up of wrongly coded DNA. This wrongly coded DNA can lead to uncontrolled cell proliferation which can then lead to an increased risk of cancerous tumours in the breasts.

MLH1 gene location on the chromosome

The MLH1 gene is located on the short (p) arm of chromosome 3 at position 21.3.


The DIRAS3 gene is part of the genetic family known as the Ras genes. This family is responsible for coding proteins that control the maturation and growth of cells. Normally these proteins will trigger the growth and maturation of the cell but the DIRAS3 protein is unique in the fact that it suppresses the growth and maturation. This also places the gene in the tumour suppressor group. This gene plays a key part in the prevention of abnormal cell growth and proliferation. The protein produced by this gene can be found in the cytoplasm or in the cell membrane where interacts with other proteins to carry out its role. The gene is inherited from both parents but only the one from the father is used. In cases of breast cancer relating to this gene it is because the one copy of the gene that is supposed to be coding the protein is lost or deactivated thus causing the lack of the DIRAS3 protein which means cells can grow and divide uncontrollably leading to a higher risk of cancerous tumours. It is unclear whether this is caused by mutations or not.

DIRAS3 gene location on the chromosome

The DIRAS3 gene is located on the short (p) arm of chromosome 1 at position 31.


The ERBB2 gene (Her-2/neu) is responsible for the production of a protein that belongs to a group of proteins called growth factor receptors. These growth factors are responsible for the stimulation of cell growth and proliferation. The protein produced by this gene is called ErbB2 growth factor receptor. It is found on the outside of the cell membrane attached to other proteins which forma complex. Growth factors attach to the receptors and they in turn send signals into the cell which triggers other genes to start the cell growth and proliferation process. When breast cancer is caused by this particular gene it is usually because of somatic mutations. 25% [4] of all breast cancers have an amplified ERBB2 gene. This means that when the gene was produced it was replicated to many times by mistake. This in turn leads to overexpression of the ErbB2 growth factor receptor protein which leads to the cell growing and dividing continuously and in turn increasing the risk of cancerous tumours.

ERBB2 gene location on the chromosome

The ERBB2 gene is located on the long (q) arm of chromosome 17 at position 12.


It is best to talk about these two genes together as they work in partnership with each other. First of all we shall start with PALB2 gene. The gene is responsible for coding a protein known as partner and localizer of BRCA2. As the name suggests, the protein works along with the BRCA2 protein. The way this protein works is by anchoring the joint protein complex to different sites in the nucleus so that the BRCA2 protein can carry out its job in DNA repair. This leads us onto the BRCA2 gene. As I just previously mentioned the BRCA2 gene is responsible for the coding of the protein which repairs broken strands of DNA. DNA can get damaged from various actions, which have been previously mentioned. Without the partnership from both genes this critical role would not be carried out effectively. There have been about 10 different mutations in the PALB2 gene that are responsible for an increased risk in breast cancer. These mutations usually relate to a smaller ineffective protein being produced that does not function correctly with the BRCA2 gene and therefor leads to DNA damage mounting up. This in turn can lead to uncontrollable cell growth and proliferation which leads to a higher risk of breast cancer. There have been over 800 mutations in the BRCA2 gene that have been identified in conjunction with breast cancer. The mutation in these genes tend to have deleted or inserted nucleotides which change the genetic code when it comes to coding the protein. An ineffective protein is then synthesised which leads to ineffective repair of broken DNA strands. This also leads to uncontrollable cell proliferation and growth which heightens the risk of cancerous tumours.

PALB2 gene location on the chromosome

The PALB2 gene is located on the short (p) arm of chromosome 16 at position 12.2.

BRCA2 gene location on the chromosome

The BRCA2 gene is located on the long (q) arm of chromosome 13 at position 12.3.


RAD51 homolog (RAD51) is a very important gene in the role of DNA repair. The protein coded by this gene is transported in conjunction with BRCA2 gene and attaches itself to the broken strand of DNA where it surrounds the break in a sheath of protein. This process is thought to be the first stage in all DNA repair. The protein is supposed to interact with the BRCA1 protein in the process of DNA repair but it is still unclear as of yet to the exact relationship they have. There have been several mutations in the RAD51 gene that are associated with the increased risk of breast cancer. A slight mutation in this gene can hinder the process of DNA repair. One reason is with the amount of relationships with other proteins it has means that its shape must remain the same otherwise these interactions won't take place. The other reason is a protein may be synthesised that won't work effectively. Both these instances can cause cells to grow and proliferate uncontrollably which in turn can lead to cancerous tumours.

RAD51 gene location on the chromosome

The RAD51 gene is located on the long (q) arm of chromosome 15 at position 15.1.


The BARD1 and BRCA1 genes are another two genes that produce proteins which work as a partnership to repair broken strands of DNA. First of all the BARD1 gene codes a protein known as the BRCA1 associated RING domain 1 protein. As suggested by the name its role is to assist the BRCA1 protein in some way. In actual fact the proteins bind to each other and therefore the complex becomes more stabilised. The BARD1 protein then directs the complex to the site of broken DNA. This is where the BRCA1 protein comes into play. The protein coded by the BRCA1 gene is known as breast cancer 1 protein. This protein binds to the site of broken DNA and fixes it. Another role that the BARD1 gene is thought to be involved in is apoptosis (programmed cell death). The BARD1 protein works in conjunction with the T53 protein to initiate this. Mutations in the BARD1 gene can lead to collapse in the relationship between the BARD1 protein and both the BRCA1 protein and the T53 protein which in turn can lead to ineffective DNA repair and uncontrolled cell growth and proliferation which can then lead to cancerous tumours. There have been over 1000 mutations found in the BRCA1 gene. Many of these have been linked to an increased risk of breast cancer. The most common result of these mutations is a shortened protein being synthesised that works ineffectively and leads to uncontrollable growth and proliferation of cells. Other mutations can result in no protein at all being produced. Both outcomes can lead to the development of cancerous tumours.

BARD1 gene location on the chromosome

The BARD1 gene is located on the long (q) arm of chromosome 2 between positions 34 and 35.

BRCA1 gene location on the chromosome

NBN & RAD50The BRCA1 gene is located on the long (q) arm of chromosome 17 at position 21.

The NBN and RAD50 genes produce proteins that work in conjunction with each other to form a protein complex that is responsible for the repair of damaged DNA. The NBN gene produces a protein called nibrin. This proteins main role in the repair of damaged DNA is to direct the RAD50 protein into the nucleus so that it can carry out its work on the broken strand. The RAD50 protein binds to the damaged DNA and holds the two broken ends together while it is repaired. The complex formed by these proteins play critical roles in tumour suppressors. In relation to breast cancer recent studies suggest that inherited mutations in the NBN gene are associated with an increased risk of breast cancer. Namely the c.657_661del5 gene mutation involved with Nijmegen breakage syndrome. People with a copy of this mutation in each cell have a threefold increase in the development of breast cancer. The mutations are thought to decrease the effectiveness in DNA damage response. This in turn can lead to uncontrolled cell proliferation and growth which increases the chance of cancerous tumours. In the case of the RAD50 genes role in the development of breast cancer it is yet unclear whether it poses a substantial enough impact or not. Granted if a smaller non-functional protein is produced then DNA repair wont work as efficiently and this could lead to the uncontrolled growth of cancerous tumours but it is yet to be proven on how big a scale.

NBN gene location on the chromosome

The NBN gene is located on the long (q) arm of chromosome 8 at position 21.

RAD50 gene location on the chromosome

The RAD50 gene is located on the long (q) arm of chromosome 5 at position 31.


The AR gene is responsible for coding a protein known as androgen receptor. Androgens (eg. testosterone) bind to these androgen receptors and the complex attaches itself to DNA where it regulates the actions that the DNA carries out. This means that genetic functions can be turned on and off. As far as relation to breast cancer there is no actual definitive proof but studies have shown that in some breast cancer cases the length of the CAG repeat in the AR gene region relates to the an increased chance of breast cancer. There have been conflicting studies where some show that a longer CAG region is responsible for the rise in risk and in other studies it shows the opposite. It is still a very thought provoking avenue that needs to be explored further in my opinion.

AR gene location on the chromosome

The AR gene is located on the long (q) arm of the X chromosome at position 12.

Somatic & inherited mutations

All breast cancers are a result of defective genes. The only difference is whether they are inherited mutations (passed on from the mother or father) or somatic mutations (mutations caused by damage to the genetic code throughout a lifetime). It used to be thought that all breast cancers were inherited but it's now been proven that even more breast cancers are caused by somatic rather than inherited mutations. This graph shows the amount of overall cases of breast cancer in the UK in 2010.

As this graph shows there were 49564 cases of breast cancer recorded in the UK in 2010. Every single one of these was a genetic mutation. Its not clear as to whether they were caused by somatic or inherited mutations though. The pie chart below shows the percentages of cases in each age group. The older the age the more likely it would have been caused by a somatic mutation otherwise the cancer would have manifested at a young age.

The amount of early inherited breast cancer cases is that small that it can't be seen on this pie chart. That should show definitively that somatic mutations cause most cases of breast cancer. It is thought that 95% of all breast cancers are somatic mutations.

Genetic screening

Genetic screening is generally only employed if there has been a history of Breast cancer in your family and it relates to a gene mutation that has shown to increase the risk of breast cancer. This means that at least one person of your immediate family has to have developed breast cancer and then agreed to be tested. Unfortunately this leaves no warning for people that may have somatic mutations as they more than likely don't fall into this category.

The actual process itself is a two-step process where blood is given to your GP and the hunt for the defective gene is initiated;

Step 1: The first step is your family members blood being tested and scrutinized to find which gene/s are mutated and likely to have caused the development of the breast cancer. This process is called mutation search.

Step 2: If any genes that increase the risk of breast cancer are found in the family member then screening tests are offered to all of the family that may have inherited them. This process is called predispositional testing

Now to make this clear, just because a positive result for gene mutation has been shown, it doesn't necessarily mean that the patient will develop breast cancer. It just gives the indication that there is an increased risk of developing it. This is to give warning to the person in question so that they can make lifestyle changes that may prevent the onset thus reducing the risk.

Lifestyle Choices and Risk Reducers

For people that have been diagnosed, with defective genes, there are lifestyle changes that can reduce the risk of developing breast cancer. Simple things like:

Maintaining a healthy weight

Eating a balanced diet

Stopping smoking

Regulating alcohol intake

There are also other risk reducers such as:

Hormonal therapy medicines

Regular screening

Protective surgery


In conclusion there are many genes that may be involved in the development of breast cancer but without proper funding for genetic screening most will be unrecognised till it is too late and the cancerous tumours have already developed. The technology is out there to be more on top of breast cancer but lack of funding and man power keep the cancer thriving. If cancer is caught early enough there is a great chance that it can be cured before it becomes life threatening which in my personal opinion begs the question why does the government waste millions of money on things like war? When they could be saving the lives of millions in the UK with properly funded genetic screening for all its population.