BRCA AND HER-2 GENES RELATION TO BREAST CANCER

ABSTRACT

Breast cancer is one of common cancers between women. Scientist discovered three genes that cause the breast cancer. Three genes which related to breast cancer are BRCA-1, BRCA-2 and HER-2. BRCA stand for BReast CAncer and HER-2 stand for Human Epidermal growth Receptor 2 gene. Mutation of the p53 gene almost cause for many kind of the cancer. Scientist developed two kind of medicine for combat with this disease. Sometimes breast cancer treated with surgery, chemotherapy, radiation and medicine when patient have developed cancer and sometimes doctors only recommended the chemotherapy, radiation and medication therapy. This paper reviews the relationship between BCRA-1, BRCA-2 and HER-2 with the breast cancer. Additionally how Tamoxifen and Herceptin help patients fight with this deadly disease. And what is the physiology behind this deadly disease and its therapy.

                   BRCA and HER-2 Genes Relation to Breast Cancer

When the cell division gets out of control cancer occurs (Cancers). The p53 gene is a tumor suppressor gene and this gene activity is stopping the formation of tumor. Cancer occurs when p53 gene mutated or person have inherited muted p53 gene. The mutated p53 genes are found in most cancer tumors. In the cell p53 gene attach to the DNA and located in chromosome 17. Muted p53 is not able to attach to DNA in effective way and the cell cannot stop dividing and cells are getting out of control to form tumor (The p53 tumor suppressor protein). Cancer cells have two important characteristics, first is that these cells are unable to stop growing, a process called Apoptosis (Chan 2006).  Normal body cells grow, divide, and die in an order. Normal cells divide more quickly during early years of a person’s life than the person becomes an adult. After that, cells only divide to replace the dying cells or to repair injuries (What Is Cancer). The pathway for normal cell growth starts with growth factor, which locks onto a growth factor receptor. The signal from the receptor is sent through a signal transducer. A transcription factor is produced, which causes the cell to begin dividing. If any abnormality is detected, the cell is made to commit suicide by a programmed cell death regulator (Oncogenes and Tumor…).The second vital characteristic of cancer cells are able to travel to other regions of the body through the blood and lymph system, a process called Metastasis (Chan 2006). Most cancers are caused by acquired mutation and occur when DNA in a cell changes during the person’s life. This can be caused by environmental influences such as exposure to radiation or toxins. These types of mutation are not hereditary because they are not in the reproductive cells. The two major types of genes that are now known as playing a role in cancer are oncogenes and tumor suppressor genes. The genes which mutated and cause normal cells to grow out of control and become cancer cells are called oncogenes. Proto-oncogene is the mutated normal genes of the cell. Proto-oncogenes are the genes that normally control how frequently a cell divides and the degree of their difference. When a proto-oncogene mutates in to an oncogene, it becomes permanently activated and the cell divides too fast, which can lead to cancer (Oncogenes and Tumor…).

Breast cancer is a growth of abnormal tissue within the breast, which is dangerous. They uncontrollably damage breast tissues by invading and disrupting normal breast tissue (Chan 2006). Abnormality of cells occurs when the check points in the cell cycle in interphase which is happen in mitosis for cell division, do not work properly, and they repeat the process of the dividing the cells. Breast cancer develops from normal breast tissues within the structures responsible for making breast milk (the lobules), or carrying the milk to the nipple (the ducts). More than 80 percent of breast cancers are ductal carcinomas. When the cancer grows through the duct walls and into the fatty tissue of the breast, it is called invasive or infiltrating ductal carcinoma. The ductal carcinoma in situ (DCIS) is noninvasive, and as a result, the risk of spreading to different regions of the body is very low. DCIS means that cancer cells are exist and increasing inside the duct, but cancer cells do not break through the duct wall. When cancer cell break through the duct wall it has become invasive ductal carcinoma. Ductal carcinoma and DCIS are often discovered by a mammogram. The lobular carcinoma in situ (LCIS) is not treated like breast cancer; when LCIS is diagnosed, it is expected that the chance of receiving an invasive type of breast cancer is roughly one percent per year. Invasive lobular carcinoma has a higher chance occurring in both breasts. Lobular cancer is harder to see on mammogram, because lobular cancer grows in between normal breast structures (Chan 2006). Lack of oestrogen receptor has consistently been associated with poor diagnosis. Most human breast cancers related to oestrogen receptor-α and the presence of this receptor is usually considered a signal of hormone dependence. Additionally, cytokines are now rising as causes that are potentially involved in breast carcinogenesis. Hematopoietic growth factors, interferon, lymphokines and chemokines are the different groups which Cytokines represents.  Many cells produce the cytokines, but the T-helper cell and macrophages are the major suppliers. Important function of the T-helper are stimulating cellular immunity and inflammation and stimulating B cells to produce antibody. Subset of T-helper cells, T-helper 1 and T-helper 2 has two different function and activities; they secrete different cytokines which help these different activities. T-helper 1 secretes cytokines, IL-2 and IFN-γ, which activates cytotoxic lymphocytes and macrophages to stimulate cellular immunity and inflammation. T-helper 2 cells secrete cytokines, IL-4 and IL-5, which stimulate antibody production by B cells (Chavey et al 2007).

There are several genes faults that can increase breast cancer risk. An individual’s lifetime risk of getting breast cancer that carries the BRCA-1or BRCA-2 gene faults could be as much as 85 precent (Define breast cancer risks. p 3293). HER-2 is an oncogene, which are necessary in managing the growth and increase of cancer. HER-2 is a non-inherited gene mutation that occurs in up to 20 to 25 percent of breast cancer. Luckily Tamoxifen and Herceptin are approved for use to reduce breast cancer risks (Ricks 2005).

The mutated gene has a dominant diffusion pattern, which means that having only one copy of the abnormal gene from either parent can potentially put a woman at risk. A parent carrying this gene has a 50 percent chance of passing it to their offspring. A mother can pass it to her sons, who can than pass it on to his daughter. Two genes have been identified for breast cancer, BRCA-1 and BRCA-2. To go through BCRA testing, a person should have had a minimum of one other relative with either having breast cancer or ovarian cancer. Otherwise, a person’s chances of carrying an abnormal BRCA-1 or BRCA-2 gene are low (Chan 2006). Before the cell becomes cancerous, a number of genetic code mistakes must have transpired (mutation). Most of these genetic mutations developed during life, either because of cancer causing substances or because of a mistake when a cell is copying its DNA before it divided into two new cells. It is possible to be born with cancer causing gene fault and it doesn’t mean person will necessary get cancer (Define breast cancer risks. p 3293). Genes called BRCA-1 and BRCA-2, when mutated, are related to breast and ovarian cancers that run in families. A major characteristic of these genes is cancers diagnoses at young ages, often under forty (Chan 2006). BRCA-1 is a fairly large gene, existing in on chromosome 17 and BRCA-2 is located on chromosome 13. In comparison, BRCA-2 is a much larger gene compared to BRCA-1. Most women with breast cancer do not have a mutated BRCA-1 or BRCA-2 gene (what cause cancer? p 119). Men who carry the BRCA-2 gene may increase risk of getting breast cancer; they are in higher risk of prostate cancer too. Men will pass the gene to their offspring; therefore their daughter who carries the abnormal gene will be at a higher risk for breast or ovarian cancer. The method for discovering these two genes is performed by a simple blood test. BRCA-1and BRCA-2 genes are called tumor suppressor genes because they contain the growth of cancer. The protein encoded by BRCA-1 and BRCA-2 genes suppress actual cells from becoming malignant by helping to repair changes that occur in other genes (Chan 2006).

HER-2 is a gene that helps control cells, grow by dividing and repairing themselves. Roughly 20 to 25 percent of breast cancers have additional copies of the HER-2 gene. This gene directs the making of special protein, called HER-2 respiration in cancer cells. HER-2 gene makes a protein receptor on the surface of the cell that can encourage growth and development of cancer cell when a growth protein connects to the receptor. With more growth of HER-2 gene, more growth receptor will form (Chan 2006). Breast cancers that contain the HER-2 mutation are called HER-2 positive. HER-2 positive breast cancer is likely to grow faster and have a greater tendency to spread throughout the body (Chan 2006). Unlike BRCA-1 or 2, there are no familial patterns involved with HER-2, meaning anyone can carry this gene. “HER-2 is a member of a family of receptors that interact with each other and various ligands to stimulate various intracellular signal transduction pathways involved in cell growth control” (Baselga, J 2001). HER-2 is found on the surface of tumor cells which exists in about one-third of all breast cancer cases (Ricks 2005). The more precise method for testing HER-2 is called FISH (Fluorescence In Situ Hybridization) and the most common test is IHC (Immuno Histo Chemistry). IHC shows the amount of protein on the cell surface whereas FISH shows the number of HER-2 genes. HER-2 is a biomarker that is tested on person’s initial breast biopsy. The activity of HER-2 encourages breast cancer growth and increase. A positive HER-2 will permit the use of Herceptin is targeting HER-2. FISH confirmation is important before Herceptin use because it will not work when FISH is negative. Herceptin is an antibody that attaches to the growth receptors on the surface of the cancer cell and blocks growth protein factors from connecting to it. This stops the cancer cell from growing and dividing. Herceptin binds to the HER-2 receptors on the tumor cell surface and this stops the receptor signaling the cell to grow and divide. Then certain immune system cells, natural killer (NK) cells, attaches to Herceptin when it is bound to the tumor cells. The NK cells then detect an abnormality, and kill the tumor cell (Herceptin, Trastuzumab). Herceptin is usually mixed with one to two chemotherapy drugs. Herceptin is an antibody designed to target HER-2 and stop that from growing. Adding of Herceptin to chemotherapy doubles or tripled the reaction rate and increase the duration of time that chemotherapy effective (Chan 2006).

In the postmenopausal the cancer risk relate to estrogen. Estrogen receptor protein is expressed in estrogen target tissues. The exogenous estrogen binds to estrogen receptor and organizes many important responses in women’s body to continue the optimal homeostasis for successful reproduction. Estrogen is also involved in the development and growth of breast and endometrial cancers and has a bad reputation in women’s health (Jordan 2007).  The aim of cancer therapeutics is without killing the patient, destroy the cancer cell selectively. To reach the goal, two interconnected strategies can be applied, critical survival targets can be identified and blocked to prevent tumor growth or a critical promoter of carcinogenesis can be identified and blocked to stop the developed of a tumor (Targeting the Estrogen receptor…..).

Tamoxifen was the first medicine that scientist found able of stop breast cancer in women who did not have the disease but who have a high risk as result of genetics or have had the disease in the past (Chan 2006). Tamoxifen is a pill that a patient takes daily, which blocks estrogen receptors. Tamoxifen is not an antiestrogen in all estrogen target tissues in the body but relatively a selective estrogen receptor modulator (Jordan 2005). For breast cancer, an antiestrogen pill, Tamoxifen, is approved for general use, which reduces the cancer risk. Tamoxifen attaches to the receptor without activating it, and thus stops estrogen from attaching to the receptor. Tamoxifen is useful in both pre and postmenopausal patients when hormones receptors are positive (Chan 2006). Tamoxifen has been shown have behavior that are independent of the estrogen receptor, with  decreasing the level of cyclic nucleotides,  bind and inhabit proteinkinase C, bind to calmodulin and inhibit cAMP phosphodiesterase action, and separation into lipids where it exerts antioxidant and membrane fluidize activities (Altan 1999).

Estrogen receptors transcriptional activities can be influenced by phosphorylation events regulated by signaling, which activates mitogen-activated kinase. Down strem signaling from the estrogen receptor also is likely to be complex and may interact/intersect with other, estrogen receptor independent, signaling pathways. Antiestrogens could influence the activities of these other pathways and alter cellular context. Whereas such events are probably not sufficient to induce an anitestrogenic effect in most estrogen receptor-negative cells, they may be necessary /permissive for signaling to a fully antiestrogenic effect in responsive cells. Thus, perturbation in the activity of some estrogen receptor independent effects could contribute to an acquired antiestrogen resistance. (Clarke 2001).  

Tamoxifen can reduce breast cancer in women with BRCA-2 mutations, but it is less clear for reducing the BRCA-1 mutation. Patients who use Tamoxifen for their therapy use this medicine roughly for five years. This medicine is better to use after chemotherapy (Chan 2006). Tamoxifen dose give a less toxin alternative in patients unable to endure the side effects of complete chemotherapy (DeGregorio 1999). Tamoxifen, like all drugs, has side effects,but the benefit of this medicine is more important. Some of the side effects of this medicine include: mild nausea, blocking estrogen receptors within the brain, and sometimes may worsen the symptoms of postmenopausal (hot flashes). Also depression or emotional imbalance is one of the rare side effects for this medicine. Tamoxifen acts as a weak estrogen on bones so that softening of bones (osteoporosis) is reduced (Chan 2006).

Breast cancer is one of the most common cancers found in women. Cancer happens in the human due to abnormalities and mutations of some genes. Three genes identified for breast cancer BRCA-1, BRCA-2 and HER-2. BRCA-1 located in chromosome number 17 and BRCA-2 located in chromosome number 13. These two genes are inherited genes and will be transmitted to an offspring if only carries by one parent. Those genes can put the women in offspring in risk of breast cancer. HER-2 is non inherited gene and anyone can carry this gene. Scientists found medicine to cure patients who have breast cancer. For reducing HER-2 breast cancer risks scientists uses the Herceptin; this medicine will attach to the increased receptors on the surface of the cancer cell and blocks growth protein factors from attaching to it. Tamoxifen is the first drug which scientists used for blocking estrogen receptors. Tamoxifen will attach to the receptor without activating them and the estrogen cannot attach to receptor. Tamoxifen reduces BRCA-2 mutation and it is better to use after chemotherapy. These medicines are the big hope for breast cancer patients. Patients could fight with their deadly disease and they will be able to live longer.    

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