Enzyme Inhibitors in Breast Cancer Therapy - Coursework Example

ENZYME INHIBITORS IN BREAST CANCER THERAPY CONTENTS Title Page………………………………………………………………………….…….1 Table of Contents………………………………………………………………….……2 Abstract…………………………………………………………………………….…....3 I. Introduction………………………………………………………………………......4 II. Metastasis and Therapy…………………………………………………………….9 A. Tamoxifen…………………………………………………………………….9 B. Aromatase and Aromatase Inhibitors…………………….………………10 C. Estrogen-Receptor Targeting…………………………….………….…….14 III. Prevention…………………………………………………………….…….………15 IV. References…………………………………………………………………….…….18 INDEX…………………………………………………………………………………...21 Enzyme Inhibitors in Breast Cancer Therapy Abstract Cancer cells are characterized as having the ability to be viable under stressful conditions. Growth and survival factors activate a variety of intracellular signal transduction pathways; these pathways play a critical role in the regulating growth, differentiation and senescence, and have been found to prevent apoptosis under many circumstances. Among all of the different types of cancer, breast cancer is the highest cause of death in women between the ages 20 and 59, having been responsible for 32 percent of all new cancer cases in 2003 (Jemal et al 2003; Brueggemeier et al 2005). In most patients, the metastases at distant sites of the body become the main cause of death. The rates of metastasis and mortality in breast cancer patients have recently decreased with the aid of early diagnosis by mammographic screening and the implementation of adjuvant therapy. Aromatase inhibitors may be used as adjuvant therapy, first-line, second-line or even third- line therapy (Cunnick et al 2001). Third-line therapy uses medicine if patients relapse after the second treatment, which followed an initial treatment. Adjuvant therapy, on the other hand, aids in the eradication of breast tumour cells that might have already metastasized to different organ systems by the time of diagnosis. I. Introduction Cancer cells are characterized as having the ability to be viable under stressful conditions. Growth and survival factors activate a variety of intracellular signal transduction pathways; these pathways play a critical role in the regulating growth, differentiation and senescence, and have been found to prevent apoptosis under many circumstances (Ripple et al 2005). The ability of cancer cells to metastasize to other organ systems results in smaller chances of curing the disease. Common phenotypes of metastatic cancer cells have been found to be (1) unregulated growth and survival, (2) decreased cell to cell adhesion, (3) increased ability in degrading the extra cellular matrix, and (4) increased motility (Zhang et al 2005). Cancer cells have been found to possess altered apoptosis signals, which are transducted by the p53 tumour suppressor gene. The said gene regulates the expression of multiply apoptosis-inducing proteins that act upon the mitochondria. Normal cells are induced to apoptosis through the intrinsic pathway, where cytochrome c is released from the mitochondria. The liberated cytochrome c binds to apoptotic protease, activating dactor-1 (apad-1), which assembles into an oligomer called the apoptosome. The apoptosome then recruits and activates caspase-9, which triggers a proteolytic cascade, resulting in cell death. In cancer cells, excessive mitotic signals activate the intrinsic pathway, as a result from mutations within signalling pathways (Mashima et al 2005; Ripple et al 2005). Among all of the different types of cancer, breast cancer is currently a major health concern in the United States alone, as it is the highest cause of death in women between the ages 20 and 59, having been responsible for 32 percent of all new cancer cases in 2003 (Jemal et al 2003; Brueggemeier et al 2005). In most patients, the metastases at distant sites of the body become the main cause of death. The risk of metastasis development increases with the presence of lymph-node metastasis, a larger-sized primary tumour with a loss of hispathological differentiation (Weigelt et al 2005). There are different types of breast cancers; the most common types are infiltrating (or invasive) ductal carcinoma, ductal carcinoma in situ, infiltrating (or invasive) lobular carcinoma, inflammatory breast cancer and lobular carcinoma in situ. Some cancer diagnoses are followed by the words in situ, meaning the cancer is contained to a single area (Oren 2007). The infiltrating (or invasive) ductal carcinoma is the most common, accounting for 70 to 80 percent of all cases, according to the National Cancer Institute (NCI). As the mass grows, it can lead to a dimpling of the breast or the nipple retracting inward. The ductal carcinoma in situ (DCIS), which is also known as intraductal carcinoma or non-invasive ductal carcinoma, DCIS refers to cancer cells confined to the milk duct of the breast with no evidence of invasion into the surrounding tissues.  DCIS is now a common diagnosis due to the widespread use of screening mammography and usually shows up as calcifications on the mammogram. In situ cancers are non-invasive and are considered the earliest stage of breast cancer (Oren 2007). Infiltrating (or invasive) lobular carcinoma can be difficult to detect because it often appears as a thickening within the breast and not a clearly defined mass. A small number of women diagnosed with infiltrating lobular carcinoma will develop the disease in both breasts. Lobular carcinoma accounts for less than 10 percent of invasive breast cancers, according the American Cancer Society (ACS) (Oren 2007). Inflammatory breast cancer is considered a highly malignant type of breast cancer. Inflammatory breast cancer can spread rapidly producing symptoms of swelling and redness and skin that is warm to the touch. The ACS estimates that approximately 1 to 3 percent of all breast cancer diagnoses are inflammatory breast cancer (Oren 2007). Lobular carcinoma in situ (LCIS), is also known as non-invasive lobular carcinoma, which is more common among premenopausal women and often develops in both breasts or in several areas of one breast. Very few women diagnosed with LCIS develop an invasive form of breast cancer. In addition, there are other rarer types of invasive breast cancers. These are: Paget’s disease, medullary carcinoma, Tubular carcinoma and Mucinous (colloid) cancers. Paget’s disease is slow-growing cancer of the areola and nipple. Starting in the milk ducts of the nipple, Paget’s disease eventually grows onto the nipple itself. It is sometimes mistaken for eczema as it can create itchiness or a crusty appearance around the nipple. This form of breast cancer accounts for about 1 percent of all cases of breast cancer, according to the ACS (Oren 2007). Medullary carcinoma is a type of infiltrating cancer which is characterized by large cancer cells and a distinct margin between cancerous and normal tissue. It accounts for less than 5 percent of breast cancers, according to the ACS (Oren 2007). Tubular carcinoma, an invasive cancer that is a slow-growing form of breast cancer that is tube-shaped. It accounts for approximately 2 percent of all breast cancers, according to the ACS (Oren 2007). Mucinous (colloid) cancer contains a mucous protein within the cancer cells (Oren 2007). There are also other extremely rare breast cancers like, Angiosarcoma, which is sometimes referred to as hemangiosarcoma, Phyllodes tumour, which is normally seen in women of middle age who have a prior medical history of fibro adenomas and primary lymphoma, in which the NCI labels these as tumour subtypes that occur in the breast, but are not considered typical breast cancers (Oren 2007). Breast cancers may be caused by any of the following risk factors: age, family history, genetic factors, Ashkenazi Jewish heritage, previous history of breast cancer or benign breast tumours, race, hormone factors, breast density, Exposure to DES (diethylstilbestrol), obesity, radiation to the chest area, sedentary lifestyle, use of alcohol and smoking. According to ACS, breast cancers occur more often to women 50 years and older and less common in premenopausal women. There is also high risk when the breast cancer occurs in a first-degree relative (mother, sister or daughter) and when the cancer occurs before age 50. A family history of ovarian cancer also increases the risk of breast cancer in women. Inheriting mutations or alterations of certain genes called BRCA1 and BRCA2 increases the risk of developing breast cancer. Breast cancer is more common in white women than in those of other races, including Hispanic, Asian or black American (Oren 2007). Hormonal influences that are believed to raise the risk include: early menarche, women who started their period before 12 years of age; late menopause, women who go through menopause after age 55; pregnancy history, women who have their first child after the age of 30 or who have had fewer pregnancies or no pregnancies.; hormone drugs, the use of oral contraceptives has been linked to a slight increase in breast cancer risk. However, women who have stopped using oral contraceptives for 10 years or more share the same risk as those women who never used them. Hormone replacement therapy (HRT) that uses a combination of estrogens and progestin may increase a woman's risk. The risk increases with the length of use. HRT has been a common treatment for some of the symptoms experienced during menopause, although rates dropped greatly after a 2002 study linked the practice to increased risks for breast cancer, stroke and heart disease. When estrogens is used alone (estrogens replacement therapy [ERT]), the breast cancer risk appears to be lower than with combination HRT including progesterone (Colditz 2004; Oren 2007) Breast cancers may include the following symptoms: rash on the skin of the breast, areola or nipple that makes it appear scaly, red or swollen; ridges, pitting or dimpling of the breast; fluid from nipples (discharge), especially containing blood; a lump or thickening in the breast; a lump in the underarm area; nipple tenderness; a change in the size or shape of the breast, and; a nipple partially or completely retracted inward (into the breast). Most breast cancer diagnoses have no pain associated. As the cancer progresses the symptoms becomes noticeable (Oren 2007). II. Metastasis and Therapy It is believed that two thirds of post-menopausal breast cancer patients possess hormone-dependent (estrogens-dependent) breast cancer, which have estrogens receptors and requires estrogens for tumour growth (Brueggemeier et al 2005). The signalling of estrogens, primarily 17β-estradiol (E2), is transmitted by estrogens receptors (ERs). ERs are members of a nuclear receptor super family, and are encoded by two distinct genes: estrogens receptor-α (ER-α) and estrogens receptor-β (ER-β) (Brueggemeier 2003). ERs consist of five individual domains: the NH2-terminal A/B domain, the highly conserved central DNA-binding domain, the flexible hinge D domain, the ligand-binding domain and the short COOH-terminal F domain. An E2-ER complex stimulates the transcriptional activity of an MMP-26 gene promoter in normal reproductive processes and hormone-regulated neoplasm, such as the breast, ovarian and endometrial carcinomas (Savinov 2006). The rates of metastasis and mortality in breast cancer patients have recently decreased with the aid of early diagnosis by mammographic screening and the implementation of aromatase inhibitors. Aromatase inhibitors inhibit breast cancer growth by reducing systemic and tumour estradiol levels (Bocardo et al 2005). These inhibitors may be used as adjuvant therapy, first-line, second-line or even third- line therapy (Cunnick et al 2001). Adjuvant therapy, on the other hand, aids in the eradication of breast tumour cells that might have already metastasized to different organ systems by the time of diagnosis. Third-line therapy uses medicine if patients relapse after the second treatment, which followed an initial treatment. A. Tamoxifen Tamoxifen was first used as a preadjuvant treatment for endocrine-responsive breast cancer. The use of this drug had significantly reduced the risk of a relapse and death in nearly all patients with estrogens-receptor (ER) positive tumours that have previously been treated. However, recent studies had discovered that five years of continuous treatment increases the risk of endometrial carcinoma, rare venous thromboses, and hot flashes (Bocardo et al 2005; (Brueggemeier et al 2005; Goss et al 2005; Jelovac et al 2005; Jin et al 2005; Winer et al 2005). Women who take tamoxifen are also commonly prescribed with serotonin reuptake inhibitor (SSRI) antidepressants. SSRIs, however, have been known to inhibit cytochrome P450, an enzyme crucial to the metabolism of many drugs, one of which includes tamoxinofen. Further research is currently being made as to resolve the side effects of tamoxifen without compromising its metabolism (Jin et al 2005). In addition, women with ER-positive tumours acquire a resistance against the said drug or even develop tamoxifen-induced tumour growth. . Patients that had first switched from tamoxifen to an antiestrogen fulvestrant. Fulvestrant, like tamoxifen, binds to the estrogens receptors competitively. However, in contrast to tamoxifen, it’s binding to the estrogens receptor leads to the degradation and down-regulation of the estrogens receptors. Further studies have revealed that aromatase inhibitors proved to be beneficial to women with advanced breast cancer who have initially been treated with tamoxifen. The efficiency of these aromatase inhibitors is being considered as an alternative to tamoxifen, combined with tamoxifen, or as a change in medication after the standard 5-year treatment with tamoxifen. Patients that had switched from tamoxifen to an aromatase inhibitor may offer advantages over continued tamoxifen treatment after a few years of taking aromatase inhibitors as this may obstruct the development of tamoxifen resistance and therefore reduce relapse rates. As a result, patients have the opportunity to receive 5 years of endocrine treatment without being fully exposed to both tamoxifen and aromatase inhibitors (Bocardo et al 2005; (Brueggemeier et al 2005; Goss et al 2005; Jelovac et al 2005; Winer et al 2005). B. Aromatase and Aromatase Inhibitors Adjuvant hormonal therapy had been the standard therapy for women with operable breast cancer. The said therapy results in significant improvements in disease-free survival, as this therapy uses aromatase inhibitors. Aromatase are cytochrome P450 enzyme complexes that synthesize estradiol from androgens. These are highly expressed in the placenta and in the granulosa cells of ovarian follicles, and its expression depends on cyclical gonadotropin stimulation. Aromatase is present, albeit in lower levels, in several nonglandular tissues, which include subcutaneous fat, liver, muscle, brain, normal breast and breast-cancer tissue. Because residual estrogen production after menopause is solely from nonglandular sources, peripheral aromatase activity and plasma level estrogen levels correlate with body-mass index in postmenopausal women. Postmenopausal women then have approximately 10 times the concentration of estradiol in breast-carcinoma tissue that in the plasma (Smith et al 2003). The highest levels of enzyme complexes are present in the ovaries of premenopausal women, in the placenta of expecting women and in the peripheral adipose tissues of postmenopausal women. In addition, the expression of aromatase was found to be highest in or near breast tumour sites (Brueggemeier et al 2005). The enzyme complex is bound to the endoplasmic reticulum of the cell and is comprised of two proteins: cytochrome P450arom, a hemoprotein that converts androgens to estrogens, and NADPH-cytochrome P450 reductase, which transfers reducing equivalents to cytochrome P450arom (Brueggemeier et al 2005). The increased expression of aromatase cytochrome P450arom observed in breast cancer tissues is associated with a change in the promoter region used in gene expression, where the promoter PII is the predominant promoter used in breast tissues. Due to the use of the alternate promoter, the regulation of estrogens biosynthesis changes from one controlled primarily by glucocorticoids and cytokines to a promoter regulated through camp-mediated pathways (Brueggemeier et al 2005). Aromatase inhibitors suppress plasma estrogen levels in postmenopausal women by inhibiting or inactivating aromatase, which synthesizes androstenedione and estradiol from testosterone. Two primary approaches have been developed to reduce the growth-stimulatory effects of estrogens in breast cancer; the first approach uses antiestrogens, which interfere with the ability of estrogens to bind to its receptor while the second decreases circulating levels of estrogens by inhibition of aromatase. Antiestrogens compete with estrogens in binding to the estrogens receptors, thereby reducing the number of the receptors available for binding to endogenous estrogens. Effective aromatase inhibitors have been developed as therapeutic agents for controlling estrogens-dependent breast cancer (Brueggemeier et al 2005). Competitive enzyme inhibitors belong to the group of steroidal inhibitors. Competitive inhibitors are comprised of molecules that compete with the substrate androstenedione, which bonds covalently to the active site of the enzyme to decrease the amount of product formed. Steroidal inhibitors that have recently been developed build upon the androstenedione nucleus and incorporate chemical constituents at different positions on the steroid. These inhibitors then bind to the aromatase cytochrome P450 enzyme in the same way as the androstenedione binds to it, which makes the inhibition successful (Coombes et al 2004; Brueggemeier et al 2005; Winer et al 2005). Another group of steroidal inhibitors is comprised of mechanism-based enzyme inhibitors. These inhibitors imitate the substrate, and are then converted by the enzyme to a reactive intermediate, which would then bind permanently to the enzyme, resulting in its inactivation. These inhibitors are also termed as “suicide substrates”, “enzyme-activated irreversible inhibitors” and “suicide inactivators”, as these produce time-dependent inactivation of the enzyme in the presence of a catalytically active enzyme. An example of such would be exemestane, which is taken orally. Exemestane is a potent steroidal inhibitor of human placental aromatase; it inhibits aromatization in vivo by 98%. A single oral dose of this drug (about 25 mg) was found to have caused a long-lasting reduction in plasma and urinary estrogens levels. The maximal suppression of circulating estrogens was discovered to be 2-3 days after intake, and persisted for 4-5 days (Coombes et al 2004; Brueggemeier et al 2005; Winer et al 2005). Another group of inhibitors are the nonsteroidal inhibitors. Nonsteroidal aromatase inhibitors possess a heteroatom that binds to the heme group of the cytochrome P450s. Initial nonsteroidal inhibitors are less enzyme-specific and inhibited (Brueggemeier et al 2005). The first group of nonsteroidal inhibitors is the first and second-generation inhibitors, which are called such because these were among the first aromatase inhibitors that had been studied in patients. Aminogluthemide was the first aromatase inhibitor. It was initially developed as an anticonvulsant; however, it was withdrawn from use after reports of adrenal insufficiency. It was found to inhibit several cytochrome P450 enzymes that were involved in adrenal steroidogenesis, and was redeveloped for use as medical adrenalectomy against advanced breast cancer. Side effects like drowsiness and rash had limited its use (Smith et al 2003). Second-generation inhibitors are usually more selective and more potent (Brueggemeier et al 2005). These include formestane and fadrozole. Each had been found to be efficient, but formestane required intramuscular injection, while fadrozole causes aldosterone suppression, which means that its use to doses that produce only up to 90 percent inhibition. Other second-generation aromatase inhibitors have never been approved for clinical use (Smith et al 2003). Third generation inhibitors that contain a triazole ring, have been successfully developed. These include anastrozole and letrozole, which are both taken orally. Anastrozole, when given a dose of 1mg/d to a patient, effectively suppresses plasma estrone and estradiol levels in postmenopausal women with metastatic breast cancer. Letrozole, on the other hand, produces approximately 99% inhibition of estrogens biosynthesis when given a dose of 2.5mg/d in patients. Letrozole was also found to produce either a partial response or stabilization of the disease in 40% of the postmenopausal women who have had endocrine treatments. These newer agents have a higher degree of specificity and are 100 to 3000 times more active than second-generation inhibitors. The third group of nonsteroidal inhibitors comprises of flavonoid derivatives as inhibitors. Flavonoids are natural plant products that are present in fruits, vegetables, legumes and whole grains. The class of flavonoids possess the benzopyranone ring system as the common chemical scaffold. Several flavonoids demonstrate inhibitory activities of the aromatase enzyme, which then lowers estrogens biosynthesis and circulating estrogens levels (Brueggemeier et al 2005; Winer et al 2005). C. Estrogen-Receptor Targeting The predominant estrogens receptor in the female reproductive tract, as well as in the mammary glands, is estrogens receptor-α (ER-α). Following the binding of estrogens to its receptor, the ER induces phosphorylation, which alters its conformation, triggers dimerization and facilitates binding of the receptor complexes, which have formed homodimers, to interact with sequence-specific estrogens response elements that are present in the promoter region of responsive genes in the target cell’s chromatin. The binding of the nuclear steroid-receptor complexes to DNA and interaction with various nuclear transcriptional factors initiate the transcription of the relevant gene to produce mRNA. The elevated presence of mRNA produces an increase in protein synthesis in the endoplasmic reticulum. These proteins, enzymes, receptors and other secreted factors, result in the steroid hormonal response that regulates cell function, growth and differentiation. Thus, estrogens enhances the growth and proliferation of certain target cells, like breast epithelial cells and estrogens-dependent mammary carcinoma cells, and induces the formation of various growth factors in established cell lines (Bruggemeier et al 2003; Shou et al 2004). The ERs have been targets for recent breast cancer treatment. The genes ERα and ERβ have been found to play complex and specific roles in the regulation of the cell response to E2, though none of which are understood in detail. A recent study by Savinov and his colleagues (2006) have identified that the estrogens-ER complex stimulates the transcriptional activity of the matrix metalloproteinase 26 (MMP-26) gene promoters. Human MMPs, also known as matrixins, are a family of zinc-dependent endopeptidases that collectively degrade extra cellular matrix and cell-surface molecules and molecular components of the basement membrane, which represents one of the most important hallmarks of cancer progression (from angiogenesis to local growth, invasion and distant metastasis formation). Physiologically, these enzymes play significant roles in normal tissue remodelling events like embryonic development, angiogenesis, ovulation, mammary gland involution and wound healing. Abnormal expression of this enzyme appears to contribute to invasion and metastasis (Duffy et al, 2000; Fernandez et al 2005). Endogenous inhibitors of MMPs have shown to suppress tumour growth, along with angiogenesis, in a variety of in vivo systems, though they differ significantly with respect to the specific angiogenic process that they inhibit. The overproduction of MMPs at tumour sites by tumour cells or stromal cells has been associated with the metastatic phenotype (Fernandez et al 2005). A study by Nozaki and his colleagues (2003) focused on the matrix-degrading activity of MMPs, which have been implicated in the pathogenesis of cancer through the promotion of angiogenesis (formation of blood vessels), tumour invasion and metastases. Because the activity of MMPs is thought to be balanced by endogenous factors that are released by tumours and stroma components, they believed that the inhibition of these degradative processes is a possible method for cancer treatment. The study made use of BAY 12-9566, a non-peptidic biphenyl MMP inhibitor that had been found to inhibit tumour invasion in vitro and angiogenesis in vivo, and had used mice as test subjects. The said MMP inhibitor was found to be antimetastatic, data had suggested that it was also had an antitumour effect, as it had inhibited angiogenesis. Thus, this study had concluded that the involvement of MMPs in the process of metastasis and angiogenesis. These genes, therefore, are appropriate targets for directed cancer therapy. Savinov’s vital research had determined that MMP-26 targets the amino-terminal A/B domain, which is also responsible for the ligand-independent transactivation function. Also, the said gene was found to be strongly up-regulated in ductal carcinoma in situ (DCIS), while it was not expressed in normal mammary epithelium. However, the expression of the said gene was found to have decreased upon the progression of the disease. Thus, the study had suggested that the expression of MMP-26 in DCIS correlates with a longer patient survival (Savinov et al, 2006). III. Prevention It is important to maintain regular physical check up and accurate medical history to track any possible symptoms or presence of cancer. Mammography is the most effective equipment used in detecting presence of breast cancers. Mammograms are x-ray pictures of the breast that can show a tumour before it is large enough to be felt. Mammograms, which use minute amounts of radiation, can also pick up abnormal micro calcifications, which are minute deposits of calcium. Most calcification deposits are not cancer. But, mammography is not a fail-safe way of detecting breast cancer. For example: a mammogram can give a false-negative result, which means that cancer is present but it does not show on the x-ray; a mammogram can give a false-positive result and areas of concern turn out not to be cancer; certain breast cancers are fast-growing and can metastasize to other parts of the body before a regularly scheduled mammograms can detect their presence. Digital mammography, a new, more accurate type of mammography is being examined as another form of breast cancer detection. This method appears to provide a more detailed image of breast tissue and may be particularly useful for women with dense breasts. Digital mammography continues to be studied for its use in breast cancer screening (Oren 2007). In addition to mammogram, there are other ways of testing presence of breast cancers, the basic methods are the breast self-examination and clinical breast exams. Ultrasonography is also used if mammogram results are inconclusive. If some areas are detected to have some abnormalities, biopsy is normally the next step of testing. Another technique is the ductal lavage, in which sample cells are passed through a catheter and examined for precancerous changes. For those breast cancer patients with an invasive form of breast cancer, the tumour should also be tested for another receptor called HER2/neu. When cancer cells over express the HER2/neu oncogene, they grow more rapidly and respond better to specific combinations of adjuvant therapy. Other tests also include: chest x-ray, bone scan, computerized axial tomography scan, magnetic resonance imaging, positron emission tomography scan, and blood tests (Oren 2007). There are many treatments available for people diagnosed with breast cancers. However, treatment of the cancer depends on different factors, like: size of tumour, location of tumour, stage of the disease, type of breast cancer, Estrogens-receptor status and progesterone-receptor levels, HER2/neu status, age, general health and menopausal status, and personal opinion and preferences of the patient. Therapy options for breast cancer include breast cancer surgery, chemotherapy, radiation therapy, biological therapy and hormonal therapy. Most breast cancers are treated with a combination of these options based on the stage and type of cancer (Oren 2007). Breast cancer surgery may include a lumpectomy or segmental mastectomy. Following this type of surgery, most women will also receive radiation therapy to destroy any remaining cancer cells within the breast. To determine whether or not the cancer has spread, many surgeons will also perform an axillary node dissection. This procedure removes some or all of the axillary (underarm) lymph nodes for inspection by the pathologist for evidence of cancer. An alternative to a complete lymph node dissection is a sentinel node biopsy, a relatively new procedure that requires removal of the lymph node where the cancer is most likely to spread first. Research indicates that if the sentinel node does not contain cancer, it is likely there will be no cancer in the remaining lymph nodes. Sentinel node biopsy may cause fewer complications associated with an axillary node dissection but it cannot be used with all patients (Oren 2007). Radiation therapy is where high-energy x-rays (radiation) are concentrated on the site of where the tumour was removed to kill any remaining cancer cells or to shrink a tumour prior to surgical removal. Chemotherapy drugs are used to treat cancer by destroying cancer cells before they divide, reproduce and spread throughout the body. Treatment with chemotherapy may be used before primary therapy to shrink the tumour (neoadjuvant therapy) or after surgery or radiation to try to prevent the emergence of undetectable cancer cells (adjuvant therapy). Chemotherapy may also be used to try to slow the spread of metastatic cancer and/or make it regress (shrink). Biological therapy is designed to bolster the body’s natural defences against cancer. Biological therapy includes the use of artificially created monoclonal antibodies such as trastuzumab. The Human Epidermal growth factor receptor 2 (HER2) gene encodes a 185-kd transmembrane glycoprotein receptor (p185HER2) and is amplified in approximately 25 percent to 30 percent in human breast cancers. When it is amplified, the gene then produces high levels of HER2 cell surface receptor expression. Trastuzumab is a recombinant monoclonal antibody that was developed to recognize (p185HER2). The results of numerous trials had indicated that trastuzumab significantly enhances the activity of first-line chemotherapy and provides a survival advantage to women with HER2-overexpressing breast cancer. This therapy can also treat HER2/neu-positive tumours by binding only to cells that over express HER2/neu and not other cancer cells or normal cells. Other biological therapies are being tried with some metastatic breast cancers (Vogel et al 2002). Bevacizumab works as an angiogenesis inhibitor, blocking the growth of blood vessels that feed the tumour through the vascular endothelial growth factor (VEGF). VEGF is the ligand for the VEGF receptor 2, and is currently a potential target for the pharmacological inhibition of tumour angiogenesis. VEGF seems to be the most important factor in regulating the growth of new blood vessels, as the secretion of VEGF by tumours had been found to stimulate the growth of endothelial cells, and increases microvascular permeability. As a result of the increase in vascular permeability, this leads to the extravasation of plasma proteins, which alters the extracellular matrix, thereby leading to the formation of new blood vessels. VEGF is expressed in a variety of tumour types, including breast cancer, mostly in invasive ductal carcinoma, metastatic ductal carcinoma and comedo-type ductal carcinoma in situ, with relatively lower expression in lobular carcinoma (Rugo 2004). When a woman is diagnosed with early stage breast cancer, one of the first things doctors want to determine is the estrogens and progesterone receptor status of the cancer. In nearly two-thirds of breast cancers, estrogens and progesterone can stimulate cancer growth and determining the cancer's receptor status at the time of original biopsy can help doctors determine which course of therapy will be most effective. If a woman's breast cancer is estrogens receptor positive, there are a number of strategies to reduce, block or eliminate estrogens in her body. Surgical techniques include prophylactic oophorectomy (removal of ovaries) and ovarian suppression (shutting down of ovaries). IV. References Bocardo F, A Rubagotti, M Putoni, P Guglielmini, D Amoroso, A Fini, G Paladini, M Mesiti, D Romeo, M Rinaldini, S Scali, M Porpiglia, C Benedetto, N Restuccia, F Buzzi, R Franchi, B Massidda, V Distante, D Amadori and P Sismondi. 2005. 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INDEX Adjuvant therapy 8, 14, 15 Anastrozole (see also nonsteroidal aromatase inhibitors) 11 Androstenedione 10 Angiosarcoma (see also hemangiosarcoma) 6 Antiestrogen 10 Apoptosome 4 Aromatase inhibitors 8, 10 Steroidal 10, 11 Nonsteroidal 11 Bevacizumab 16 Breast cancer 4 – 7 Cancer cells 3, 4 Chemotherapy 15 Cytochrome c 4 Cytochrome P450 8, 9 Ductal carcinoma 4 Ductal carcinoma in situ 4 Ductal lavage 14 Estradiol 8 Estrogens receptors 8, 12 Exemestane (see also steroidal aromatase inhibitors)11 Flavonoid (see also nonsteroidal aromatase inhibitors) 12 Fulvestrant 9 Hemangiosarcoma (see alsi angiosarcoma) 6 HER2/neu 14, 15 Infiltrating lobular carcinoma 4, 5 Inflammatory breast cancer 4, 5 Letrozole (see also nonsteroidal aromatase inhibitors) 11 Lobular carcinoma in situ 4, 5 Mammograms (see also Mammography) 14 Mammography ( see also Mammograms) 14 Mastectomy ( see also 15 Medullary carcinoma 5, 6 Matrix Metalloproteinase 26 (MMP-26) 12, 13 Metastasis 3, 8 Microcalcifications 14 Mucinous cancers 5, 6 Oophorectomy 16 p53 tumour suppressor gene 3 Paget’s disease 5 Phyllodes tumour 6 Tamoxifen 9 Trastuzumb 16 Tubular carcinoma 5, 6 Read More