The mostly affecting cancer in female is Breast Cancer after Lung Cancer in all over the world. The researchers had proved the breast cancer is mostly prevailing all over the world especially in women. For example in the entire Cancers 32% are the Breast Cancer cases were found in United Kingdom. In 2003, UK there was 36,500 different cases of Breast Cancer. There is also a possibility in men suffering from this disease. For the diagnosis of the breast cancer one should know the molecular basis of the disease to treat it.
There are several methods of treatment like, Surgery, Radiotherapy, Chemotherapy, etc. These treatments are done depending on the type of the cancer. According to the Molecular Mechanism of Drug Actions, Hormonal Therapy and Biological Response Modifiers were also used to treat the disease. This includes SERMs and Aromatase Inhibitors. Hence the molecular basis of the disease and the type of drug treatment and what kind of mechanism through which drug acts on the disease are clearly summarized
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Cell division is the main process in the Human Body. This process replaces the old cells with new cells. If the growth of the new cells exceeds the old cells a tumour will develop, which automatically leads to the cancer with aggressive growth of cells.
Breast Cancer is occurred with excess growth of cells in the milk ducts or milk glands. If the Breast Cancer spreads to the other parts of the body it is known as IBC (Invasive Breast Cancer), if does not spread and limited to the ducts it is known as NIBC (Non-Invasive Breast Cancer). It has the chance to develop in to invasive breast cancer if it is not treated.
Breast Cancer is the most common cancer for females. In England among the entire Cancers 32% are the Breast Cancer cases. In 2003, UK there were 36,500 different cases of Breast Cancer, mostly breast cancer occur in postmenopausal women as 80% of the cases were occurred in postmenopausal women.
MOLECULAR BASIS OF THE DISEASE
In the human cell G1, S, G2 and M are the different phases involved in the cell circuit. S phase is the synthesis phase in which DNA is synthesised. G1, G2, are the gap phases and M Phase is Mitotic phase. These sequential phases' functions in response to the oncogenic stimulations also called as growth factors (C Wang et al. 2004). In these sequential phases different check points are involved, which requires a favourable growth factor or oncogen for the transition of the cell cycle. In the cancer the breast cancer susceptible genes (BRCA1 and BRCA2) are involved in DNA repair (RS Maser et al. 2002). This repairing leads to the gene loss, gene amplification, chromosomal translocations. Tumour is the consequence of the activation of an oncogen and inactivation of tumour suppressor genes (DI Evan et al. 2000). In breast cancer number of factors are related which influence the tumour. For the treatment of the cancer knowing its molecular basis is important.
It is a tumour suppressor gene. It is involved in the gene transcription. Cell division and growth repairing are done in the DNA through this protein. Disturbance in this p53 breaks the checkpoints, which leads to genomic instability and continuous the development of damaged cells (SP Hussain et al. 1998). The protein product of it is a phospho-protein contains 393 residues with 4 domains and it is located in the chromosome (DP Lane et al. 1999).
Mutation in p53 can occur in different ways like Nonsense, Messene, and Mutations in breast cancer. The important altered p53 genes are MDM2 and p21. These conditions are favourable in results the development of tumours (C Osborne et al. 2004).
In the development process of the tissue Bcl-2 utters in every tissue. In adults it is present in the reserved cells of the breast tissue. Normally it is expressed in mammary epithelial cells in un-pregnant and pregnant women. But in the stage of lactate, its presence is not found (DM Hockenbery et al. 1991). The Bcl-2 contains both pro-survival and pro-apoptotic family members (MD Adams et al. 1998). Bcl-2 gene is present in the chromosomal translocation, its main body is present in the cytoplasm and it involves in maintaining the mitochondrial permeability. Adult breast glands require Bcl-2 for its anti-apoptotic function. It also protects cells from various stresses and recovering the cells to the normal state from DNA damage (YJ Lee et al. 2000).
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Bcl-2 forms a hetero-dimer with the pro-apoptotic member of Bcl-2 family. In the pro-apoptotic condition Bax is over expressed in the cytoplasm leading to the formation of Bax homo-dimer, resulting in the exit of Cyto-chrome C and leading to the apoptosis of the cell. This condition leads to the cell alterations (DI Quinn et al. 2005).
It is the anti-apoptotic protein which interacts with Bcl-2. It also binds ER receptors and causes apoptosis. But its main function is oncogenesis and progressing the disease Breast Cancer. It interacts with Bcl-2 and it is unregulated by P53 (SC Tang et al. 2004). Bag has 6 proteins but 4 out of them were identified (Bag-1, -3, -4 and -6). There interacts with (Hsc70/Hsp70). It has 4 isoforms Bag-1L, Bag-1M, Bag-1s and Bag-1L is situated in nucleus (H Dong et al. 2002). It binds with different intracellular protein which controls the process of cancer cells division, migration and survival. There is a positive correlation between the ER, PR, & Bag-1. It has been shown that 92% of Bag-1 is increased in breast cancer (SC Tang et al. 1999). It will express that Bag-1 is the molecular indicator for the survival of the breast cancer and prognostic factor in maintaining breast cancer (BC Turner et al. 2001).
P27 & SKP2:
P27 is a virus protein and SKP2 is an S-phase kinase associated protein (AA Russo et al. 1996). There are proteins are the opposite regulators of the cell cycle. These proteins are important, that if loss of these proteins increases the tumour behaviour (S Signoretti et al. 2002).
The HER-2 is present in different tissues and it helps tissue in proliferation development and differentiation. It is a proto oncogen situated on the chromosomes (T Cooke et al. 2001). 20 - 40% of breast cancer patients over expression of HER-2 and it are over expression leads to the development of breast cancer (A Hamilton et al. 2000).
The Estrogens Receptors (ER):
The estrogen receptors have an important function on male and female physiology. The estrogen receptors play a vital role in the cell proliferation and cell differentiation (A Gompel et al. 2004). By targeting the tissues it can be divided into two groups, Classical and Non Classical (JA Gustafsson et al. 1999). In human memory glands estrogen receptors were found in epithelial cells and as well as on stromal cells. The tumour genes were thought to be controlled directly or indirectly by estrogen receptors, which alter the nature of the disease (CK Osborne et al. 1998).
Drug Treatment: There are different types of treatments for Breast Cancer. They are,
Surgery - In surgery the whole breast is removed and it is called as Mastectomy. If only lump in the breast removed it is known as lumpectomy. Also it is preferred to remove lymph gland from the axialla.
Radiotherapy - In radiotherapy hi-energy X-rays were used to destroy the cancer cells. Most probably this treatment is done after Mastectomy. it is not a complete treatment, it only plays a vital role in the area that is being treated with surgery. It has some side effects.
Chemotherapy - In this treatment anti cancer drugs were used to kill the cancer cells. In some patients if the tumour is large chemotherapy is preferred and then the surgery is done. There are several chemotherapy drug combinations so normally they were given via vein.
Hormonal Therapy - Several hormones were used in this therapy. The hormones are known as selective estrogen receptor modulators if they bound to the estrogen receptors in the breast tumour cells. Examples: Tamoxifen, Evista, Fareston. if they prevent the production of the estrogen hormone they were known as aromatase inhibitors. Ex: Aromasin, Femara, Arimidex, Megace.
Biological Response Modifiers - These kinds of drugs used to bind with the proteins on the tumour cells by suppressing its growth. Ex: Herceptin
Other Hormonal Therapies - Other than SERMs and aromatase inhibitors there are different hormonal therapies which were used to treat the breast cancer. Ex: Zoladax, Fasladex.
The drug fasladex is used by the patients who had become resistant to the drug Tamoxifen. This fasladex kills the estrogen receptors in the tumour cells, instead of binding to the estrogen receptors.
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Molecular Mechanism of Drug Actions:
The Drugs which were used to treat for Breast Cancer have different molecular mechanism, to deliver their action which is important in the treatment of the disease in patient.
SERMs (Selective Estrogen Receptor Modulators): Almost all Breast Cancers depends upon Estrogen Hormones for their survival, growth and reproduction (BJA Furr et al. 1985). These hormones will be bounded to the estrogen receptors of the tumour cells and mimic their effect, which leads to the blocking of estrogen hormones stopping hormones supply to the tumour cells. Due to this effect the tumour cells were starved as if they were depended upon the estrogen hormones (CD Love et al. 1999).
Tamoxifin is the most commonly used SERMs in the treatment. It is used to treat both the early and advanced stages of the tumour (JF Forbes et al. 2008). Recent clinical trials show that usage of tamoxifin can reduce the risk of cancer by 49% in post menopausal women. Tamoxifin will bind to the nuclear receptor which leads to the activation and dimerizetion, which binds on to the estrogen receptor and regulates to the gene action (AS Coates et al. 2000).
There are several other SERMs which were prescribed example evista, which is also used to treat osteoporosis.
Side Effects: Due to the extensive use of Tamoxifin cancer may resistant to this drug. It has common side effects like fatigue joint pains, fluid retention which cause ankle and finger swelling.
Aromatase Inhibitors: These drugs will bind to the bodies' aromatase enzyme, which is the main producer of estrogen. The main mechanism involved in these drugs is, "They bind to the enzyme aromatase and inhibit the production of estrogen" which prevents the supply of estrogen to the tumour cells (M Dowsett et al. 1998). Ultimately the tumour cells starve for the estrogen hormone. There are several drugs used to treat advanced tumour. Ex: Arimidx. It is the drug commonly used to treat breast cancer. It is being administered through intravenously. Recently it is shown that aromatase inhibitors are more effective than tamoxifin (F Boccarido et al. 2005).
Side Effects: It has some common effects like Head-ache, Insomnia, High Blood pressure, Arthritis and Diarrhea.
Biological Response Modifiers: These drugs used to bind with the proteins of tumour cells by preventing the growth of the tumours. Herceptin which is a monoclonal anti-body, which is attached to Her2 a protein which is usually found in breast tumour cells (R Dent). Herceptin when bound to Her2 receptors it stops the tumour cells to grow and divide. It is administrated by the patients who shows the over expressions of Her2 protein.
Side Effects: Some common side effects like weakening of heart muscles, abdominal pain and anemia etc,
Other Hormonal therapies:There are several other hormonal therapies which are used to treat the breast cancer which depends upon the estrogen. For example Zoladex. It treats breast cancer and prostate cancer. Its mechanism is by blocking the estrogen hormone from tumour cells. It is injected through the skin and it is a systematic treatment. Faslodex is another hormonal therapy used by the patients who became resistant to Tamoxifin (GM Clark et al. 1999).
Side Effects: It shows the side effects like breast swelling, vaginal dryness and absence of menstruation.
There has been lot of developments in the treatment of breast cancer done in past and researches are going on for future. The researchers are based on the level of molecular and cell biology. The future prospects have been developing for more effective treatment and less cost. And the future aspects Immunotherapy and Gene therapy are particularly and currently are exciting areas. New developments are evolving to reduce the mortality rate with the use of monoclonal anti-bodies, which are meant to be the effective measures of treatment (A Gordon et al 1997).
Immunotherapy: It is rapidly developing with widely spread researchers on cancer treatment. It is used mainly by two principles; one is the use of Cite specific anti bodies which targets Chemotherapy substances at tumour cells. Secondly, through cell mediated immunity systems by which host can reduce the tumour (AM Scott et al. 1997). There have been a lot of cases in which the patients have responded to this form of treatment (RT Skeel et al. 1997). Mainly monoclonal anti bodies which were used in this are toxins of bacterial or plant origin (DJ Lindner et al. 1997). There is another approach by using monoclonal anti bodies which are, by blocking the growth factor receptors. And in some recent cases there have been used both targeted anti bodies and cell therapy (PG Coulie et al. 1997).
Gene Therapy: There is been a lot of progress in gene therapy in last few decades (GD Schmidt-wolf et al. 1995). Some current researchers are been made on the p53 tumour suppressor gene. And they are inventing the ways through which it can be delivered to the tumour cells (RK Schmutzler et al. 1997). This kind of delivery system requires adenoviruses (BM Putzer et al. 1998).
Cell Therapy: This involves the modification of cell in order to stop the proliferation of tumours. Researchers are been going on which includes vitamin D3 isomers, as the tumour cells meant to have vitamin D3 receptors (M Koike et al. 1997). This kind of therapy is also included by blocking IGF receptors (S Neuenschwander et al. 1995). The most recently and impotent research area is on Telomerase. Telomerase are the elements or substances that were present in chromosome and involves in cell ageing. The tumour cells which are immortal are meant to have high levels of Telomerase which stops the normal process of the cell ageing by destroying Telomerase present in the cells (A Hoss et al. 1998).
Complimentary Therapy: By developing new techniques and treatments is not the ultimate method of decreasing the mortality rate of breast cancer in patients by providing awareness in the people. So they can improve the knowledge regarding the disease is more important (MA Ashby et al. 1996). As there are studies which clearly displays that this kind of therapy modifies endocrine and immune system which may have a proper impact on the disease (G Vanderpompe et al. 1997).
In the above discussed essay Molecular Mechanism of Drug Treatment of Human Breast Cancer, the molecular basis of the disease is explained by the interaction of the oncogens or growth factors on the target tissue. The importance of the growth factors like p53, Bag-2, Bcl-2, The HER-2, p27 and skp2, and the significance of their effect on the disease are clearly discussed. The various kinds of drugs that are used to treat the diseases and mechanism of the action through which they were acting successfully to treat the disease were also discussed. For example, SERMs, Mimic the estrogen activity, aromatase inhibitors bind to the aromatase enzyme and stop the production of estrogen hormones, which will be helpful for survival of tumour tissue.
Several methods and technologies were used to treat the disease and researchers are inventing latest techniques and methods to treat the disease with low cost and for effective treatment. For this several researchers were going on Immunotherapy, Gene Therapy, and Cell Therapy for better results.