الفهرس 
INTRODUCTIONOnly 14 pages are availabe for public view
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Abstract
Breast cancer is the most frequently diagnosed cancer and it is the leading cause of cancer death among females worldwide. Although the aetiology of breast cancer is unknown, copious predisposing risk factors for the disease have been established. These factors can be assigned to these major categories; age, excessive exposure to estrogens and deficiency in maintenance of genomic integrity. Options for treating breast cancer vary according to the stage of the disease. These options are: surgery, radiotherapy, chemotherapy, hormonal therapy and targeted therapy.
Studies concerning nuclear receptors have revealed the existence and implication of several additional nuclear receptors other than estrogen and progesterone in the biology of breast cancer. Peroxisome proliferator activated receptors (PPARs) are one of them. Therefore, PPAR ligands can be used as alternative therapies to treat breast cancer.
In view of such considerations, the design of the present work was set to detect and compare the effect of fenofibrate (PPARα ligand), pioglitazone (PPARγ ligand) and omega-3 (PPARα and γ ligand) on the growth and proliferation of mammary carcinoma induced in female rats. Moreover, the current work was also meant to investigate the possible mechanisms of action of all used drugs to achieve best therapeutic management of breast cancer.
Fifty female albino rats weighing between (90-110g) were used in the current study. Ten rats were allowed to feed normal diet and received only 1 ml of sesame oil orally to serve as plain normal control. The other forty rats were subjected to induction of mammary carcinoma by administering a single dose of 20mg of the 7, 12 dimethylbenz(α)anthracene (DMBA) suspended in 1ml sesame oil / rat via an oral gavage syringe. Starting from the 6th week after DMBA administration, rats were palpated at weekly intervals to monitor the appearance of mammary tumors which took 24-48 weeks to appear and to reach a considerable size. Then rats were randomly assigned to four experimental groups (10 rats each) as follows:
Group I: Untreated tumor-bearing control group; rats received 1ml of 2% gum acacia/day orally.
Group II: Fenofibrate-treated group; rats received fenofibrate 100 mg/Kg/day orally.
Group III: Pioglitazone-treated group; rats received pioglitazone 120 mg/Kg/day orally.
Group IV: Omega-3-treated group; rats received omega-3 1.5 g/day /rat orally.
Fenofibrate, pioglitazone and omega-3 were dissolved, suspended or emulsified in 2% gum acacia. All the drugs and control vehicle were given daily for 28 successive days (experimentation period). Tumor volumes were determined at the start of the therapy and at weekly intervals during the treatment period to assess the effect of different drugs on the rate of tumor growth. At the end of the experimental period and after an overnight fast, blood samples were collected from the retro orbital venous plexus of the rat. Serum samples were separated and used for estimation of vascular endothelial growth factor (VEGF) levels. Animals were then sacrificed, tumors were excised, and tissue sections were prepared for histopathological (H&E) examination and immunohistochemical detection of Ki-67 (proliferation marker) expression. Tumor tissues were also used for biochemical assay of VEGF, caspase-3 (apoptosis marker) and cyclooxygenase-2 (COX-2) levels. In addition, livers were isolated, homogenized using the specific homogenizing solution and used for determination of malondialdehyde (MDA) level and reduced glutathione (GSH) concentration.
Results of the present work revealed that the untreated DMBA-induced mammary carcinoma-bearing control rats had a marked, progressive increase in tumor volume along the course of the experiment. Treatment with fenofibrate, pioglitazone or omega-3 significantly reduced the rate of mammary tumor growth all through the experimentation period. The most favorable response was obtained in the group of rats treated with omega-3. On the other hand, fenofibrate treated group showed marked decrease in tumor growth rate within the 4th week of treatment.
The significant reduction in the rate of breast cancer growth obtained by fenofibrate, especially within the 4th week of treatment, was attributed to the marked inhibition of angiogenesis, induction of apoptosis, noticeable antiproliferative effect, potent antioxidant and lipid peroxidation- lowering effects, and reduction of tumor-associated inflammatory effect. The pronounced antitumor effects of fenofibrate have been established to be mostly PPARα- dependent mechanisms. However, PPARα- independent mechanisms may explain part of fenofibrate antitumor effects.
Pioglitazone therapy also significantly reduced the rate of growth of mammary carcinoma. This was achieved via its antiangiogenic, proapoptotic, antiproliferative, anti-inflammatory, antioxidant and lipid peroxidation-lowering effects. The anticancer effects of pioglitazone were mainly attributed to PPAR-γ agonism as well as due to the drug itself.
Furthermore, results of the present work demonstrated that omega-3 supplementation has shown the least rate of mammary tumor growth among all the studied groups. This was elicited through various mechanisms including the marked anti-inflammatory effect, induction of apoptosis, antiproliferative effect, inhibition of angiogenesis, antioxidant and lipid peroxidation-lowering effects. The molecular mechanisms which account for these biological effects are complex and diverse including being PPAR α, γ dual agonist in addition to many other mechanisms.
Taken together, this work provided an evidence that each of fenofibrate, pioglitazone and omega-3 exerted anti-tumor effect on a well-established, induced-breast cancer in rats via numerous mechanisms of action