الفهرس 
IntroductionOnly 14 pages are availabe for public view
 |  | from | 197 |  |  |
| | | from | 197 | | |
Abstract
Breast cancer is a multifactorial disease in which malignant cells form in the tissues of the breast, with two million new cases were detected globally accounting for 25% of all female cancers and second leading cause of cancer death. Breast cancer may be presented as breast pain, lump, change in breast shape, nipple discharge, dimpling, red scaly patch of the skin, malaise, bony pain, and weight loss. Physical examination should include Nipple changes, asymmetry, obvious masses, skin changes such as; dimpling, erythema, peau d’orange and the cervical, supraclavicular, and axillary lymph node are palpated for adenopathy. Several risk factors predispose to breast cancer including environmental factors such as Exposure to ionizing radiation due to nuclear war, medical diagnostic, or therapeutic procedures, old age, life style as diet with high amounts of fat, caffeine, and red meat and physical activity, hereditary mainly BRCA1 and 2 which account only for 5% to 6% of breast cancers, alcohol consumption, tobacco smoking, the more menstrual cycles as early menarche and late menopause, hormone replacement therapy and oral contraceptives, obesity, mammographic density, benign breast disease, previous cancer history and hyperplasia. The pathogenesis of breast Cancer is driven by genetic and epigenetic alterations in the signaling pathway leading to an alteration in cell death, proliferation, division, differentiation, and motility. The predominant signaling pathway are estrogen receptor (ER) signaling, deletion mutations and loss of function in the BRCA genes lead to decreased DNA repair efficiency and possibly give rise to the expansion of cancerous cells, Warburg effect in which Cancer cells have a higher uptake of glucose and more dependent on the anaerobic glycolysis to produce ATP, oxidative stress both affect the initiation and development of breast cancer by attacking DNA and inducing DNA damage, inflammation affecting cell proliferation, differentiation, tumor metastasis, angiogenesis and uncontrolled proliferation and reduced apoptosis. Pathology of Breast cancers can be divided into two broad classifications, carcinomas and sarcomas. Based on criteria of pathological features and invasiveness, common breast cancers can be divided into three major groups: non-invasive (or in situ), invasive, and metastatic breast cancers Polyaromatic hydrocarbons (PAHs) have been implicated as etiologic agents in breast cancer. Exposure occurs through the smoking of tobacco, inhalation of polluted air, and ingestion of charbroiled foods. These PAHs are metabolized and transformed into DNA-attacking metabolites in the body, producing DNA mutations which are found in human breast tumors. The synthetic PAH (DMBA) induces the production of free radicals that induce carcinogenesis in rodents that resemble human cancers as regard to morphology and histology. Therefore, DMBA induced mammary carcinogenesis is an ideal model of experimental breast cancer. DMBA induced mammary carcinomas are positive for both ER and PR, with better chance of breast cancer induction when administrated to young rodents. Mechanisms supposed for DMBA carcinogenicity are point mutation and disturbance in cellular oxidant-antioxidant balance. DMBA induced mammary tumors includes adenocarcinoma which is more frequent among breast, myoepithelial carcinomas and myoepithelioma and ductal carcinomas. In most of the animals, the tumors were highly infiltrative, with high mitotic activity, hemorrhage, and extensive necrosis.To study mammary carcinogenesis, doses of 3, 6, and 9 mg of DMBA (1 mg per week) are suitable. Raloxifene (RAL) is a selective estrogen receptor modulator (SERM) which is approved by FDA for prevention and treatment of osteoporosis in postmenopausal women. Raloxifene is one of only two agents approved by the (FDA) for risk reduction of breast cancer in women at increased risk of this disease, not used for duration longer than 5 years for primary breast cancer prevention. RAL reduces invasive breast cancer by 44% and invasive ER-positive breast cancer by 55%. It has anti-inflammatory, Antioxidative, apoptotic and antitumor effects. Sodium oxamate is an LDHA specific inhibitor that induces G2/M cell cycle arrest and promotes apoptosis preventing the conversion of pyruvate to lactate can potentially produce changes in the tumor microenvironment that possibly overcome cancer cell proliferation, metastasis, inhibition of the immune response, blocking tumor growth, maintenance, and progression. It has a wide range of beneficial biological activities including antioxidative, anti-inflammatory, apoptotic and antitumor effects. The aim of this work was to study the potential role of sodium oxamate, as LDH inhibitor, alone or in combination with raloxifene Hcl in prevention of DMBA induced breast cancer in mice. This study was performed on 48 female swiss albino mice weighing 20-25 g, divided randomly into 6 equal groups (8 mice for each) as follows: group 1: was served as a normal control group. group 2: received a vehicle of olive oil 0.2 ml /week orally + daily i.p injection of 0.25 ml sterile saline group 3: breast cancer group received DMBA in a dose of 1.0 mg /week for 6 weeks by oral gavage + daily i.p injection of 0.25 ml sterile saline. group 4: breast cancer group received DMBA in a dose of 1.0 mg /week for 6 weeks by oral gavage and was treated by Raloxifene HCL i.p. injection in a dose of 3mg/kg/day. group 5: breast cancer group received DMBA in a dose of 1.0 mg /week for 6 weeks by oral gavage and was treated by Na oxamate i.p injection in a dose of 300 mg/kg/day. group 6: breast cancer group received DMBA in a dose of 1.0 mg /week for 6 weeks by oral gavage and was treated by both Raloxifene HCL i.p. injection in a dose of 3mg/kg/day & Na oxamate i.p injection in a dose of 300 mg/kg/day. Treatment protocol for groups 3, 4, 5, 6 was started from 1st day of induction until the end of the experiment on day 42nd. The mice were observed weekly and: 3- The body weight of each mice was recorded weekly until the end of the experimental period. 4- After euthanization, All macroscopic mammary tumors were excised, and the tumor volumes were measured (length x width) to the nearest 0.1 mm, using calipers and were calculated according to the following formula: Tumor volume = 1/2 (length x width2). At the end of the experiment (after 6 weeks), the mice will be euthanized by the administration of pentobarbital sodium (150 mg/kg, i.p.) and lidocaine (10 mg/kg, i.p.), followed by breast tissue dissection and washed with phosphate-buffered saline (PBS) solution, pH 7.4. to remove any red blood cells and clots, The abdominal glands were fixed in 10 % formalin and processed for the examination of histopathological changes by light microscope and immunohistochemical expression of Bcl2 while the remaining glands were stored at - 80 ºC until prepared for the assessment of the following tissue parameters: 5- LDH level. 6- TNF alpha level. 7- Reduced glutathione (GSH) levels. 8- Malondialdehyde (MDA) levels. Results of the present study revealed the following: In the present study, the results of DMBA treated group (group 3) when compared to vehicle received group (group2) showed significant increase in tumor development percent, breast mass volume, tissue LDH level, tissue TNFα level, tissue MDA level and Bcl2 expression while there was a significant decrease in tissue GSH level, body weight.The histopathological findings in DMBA treated group (group 3) of this study showed sheets of malignant ductal cells surrounded by desmoplastic reaction, Higher magnification show malignant ductal cells exhibiting pleomorphism, hyperchromatisa, and abnormal mitotic figures. In this study, the results of RAL treated group (group 4) when compared to untreated DMBA treated group (group 3) showed significant decrease in tumor development percent, breast mass volume, tissue TNFα level, tissue MDA level and Bcl2 expression while there was a significant increase in tissue GSH level, and there is no significant difference in tissue LDH level. RAL treated group showed non-significant difference in body weight as compared to DMBA treated group (group3). Section of breast showed residual malignant cells with individual cell necrosis with areas of hyalinization. This BC prevention can be attributed to its antioxidant, anti-inflammatory and apoptotic effect proved in this study. The breast tissue protection observed with Na oxamate is believed to be due to its antioxidant, anti-inflammatory and apoptotic effects proved by the results of Na oxamate treated group (group5) when compared to DMBA treated group (group3) showing significant decrease in tumor development percent, tumor volume, tissue LDH Level, tissue TNFα level, tissue MDA level and Bcl2 expression a while there was a significant increase in tissue GSH level and significant increase in body weight as compared to DMBA treated group (group 3). Section of breast showed residual malignant cells with a focal area of necrosis with large areas of hyalinization and some lymphocytes (a sign of good prognosis). The combined RAL& Na oxamate treated group (group 6) showed evident antioxidant, anti-inflammatory and apoptotic effects represented by significant decrease in tissue LDH level, tissue TNFα, tissue MDA level and Bcl2 expression and significant increase in tissue GSH level when compared to the DMBA treated group (group 3). Moreover, histopathological examination of combined RAL& Na oxamate treated group (group 6) showed focal residual malignant cells with massive necrosis, wide areas of hyalinization and calcification with many lymphocytes (a sign of good prognosis), that is reflected on the clinical outcome as regard to change in percentage of body weight change which showed significant increase in the percentage of body weight at the end of the study as compared to the DMBA treated group (group 3) and there was significant decrease in percent of breast mass and breast mass volume developed as compared to the DMBA treated group (group 3). Section of breast showed residual malignant ductal cells showing apparent weak positive Bcl2 staining. When the combined RAL& Na oxamate treated group (group 6) was compared to both the RAL treated group (group 4) and Na oxamate treated group (group5), it exhibited superiority in anti-inflammatory, antioxidant and apoptotic effects represented by significant decrease in tissue TNFα level, tissue MDA level and significant increase in tissue GSH level and non-significant difference in Bcl2. The combined RAL& Na oxamate treated group (group 6) showed significant increase in the percentage of body weight at the end of the study as compared to RAL treated group (group4) while showed non-significant difference in percentage of body weight change as compared to Na oxamate treated group (group5). The combined RAL& Na oxamate treated group (group 6) showed non-significant decrease in the percent of the breast mass developed and breast mass volume as compared to RAL treated group (group 4) and Na oxamate treated group (group5). But as regerd to tissue LDH level, the combined RAL& Na oxamate treated group (group 6) show significant decrease in tissue LDH level as compared to RAL treated group (group 4) and a non-significant difference as compared to Na oxamate treated group (group 5).