الفهرس 
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Abstract
Breast cancer is the most frequent cancer in women, responsible for up to one-third of all recent cancer diagnoses. Breast cancer is the leading cause of death among women in developing countries, with one out of every eight women suffering from the disease. Cancer develops when cells lose their ability to die at the appropriate time and stop dividing. Apoptosis is a physiological mechanism that keeps cell populations in tissues under control. The goals of the current study were to develop a reliable protocol for breast cancer induction in mice, evaluate the anticancer activity of BFB against mammary tumors induced by dimethylbenz(a)anthracene (DMBA) in female mice, and reveal the underlining mechanism/s of breast cancer induction and treatment.
The treatment with DMBA resulted in a considerable reduction in body weight gain, which was significantly reversed by the BFB, whereas TAM had no effect on the DMBA-induced weight gain reduction. Although the DMBA reduced body weight gain, it increased the relative weight of the liver and spleen significantly. When compared to the DMBA group, the BFB was able to lower the weight of these organs and nearly restore the liver and spleen relative weights to normal control values.
Many tumors with central necrosis were found in the DMBA group. Some mice in the DMBA group developed breast cancer that spread to their lungs, digestive tract, uterus, and ovaries. Hepatosplenomegaly was observed in the DMBA and DMBA/TAM animals, which was accompanied by a substantial rise in the relative weights of the liver and spleen. The i.p. injection of DMBA induced fluid accumulation in the peritoneal cavity, resulting in the death of all animals. BFB treatment resulted in complete loss of nasal hair in all animals in both the DMBA/BFB and BFB groups.
The BFB reduced the tumor incidence, multiplicity, and number of total tumors, and average tumor size. TAM was much less effective. The group administered with BFB only had 30% mortality rate over a period of 42 weeks. The mice in the control and BFB groups did not show any spontaneous tumors. The treatment of BFB reduced the mortality while TAM reduced it to a lesser extent. Most of the mortalities occurred during the treatment of the DMBA.
CDK1 and HER2 were significantly upregulated in the DMBA group, while p53, p21, ESR1, and CAS3 were significantly downregulated. After DMBA exposure, BFB treatment reversed the effects of DMBA, resulting in significant downregulation of CDK1 and HER2 expression and overexpression of p53, p21, ESR1, and CAS3. In comparison to the DMBA group, TAM treatment resulted in significant downregulation of CDK1 and HER2 but the relative expression of p53, p21, and CAS3 was non-significantly increased after TAM. After TAM, the ESR1 was significantly upregulated.
Due to the invasion of malignant cells through the basement membrane of some breast ducts, the DMBA resulted in the formation of several new ductules. DMBA caused ductal carcinoma to form, with polymorphism and mitotic activity in tumour cells. Tumors were graded as invasive type III, with central necrosis and mild fibrosis. The effects of DMBA were reversed when BFB was given and normal mammary glands and epidermis were seen in the animals. The majority of TAM-treated mice developed ductal carcinoma, with newly created ductules, mild fibrosis, polymorphism, mitotic activity, and cyst development. BFB alone did not induce any deterioration in the structure of mammary glands; normal acini structures were seen. The dermal layer showed follicles in the deep dermis and acini. The tumors of DMBA group were from grade III which were also found in DMBA/TAM in addition to grade II tumors while tumors of DMBA/BFB group were only at grade I. In comparison to DMBA and DMBA/TAM groups, BFB reduced the mitotic activities almost into half, stopped the appearance of any polymorphism and prevented the formation of any necrotic foci which were clearly seen in DMBA and DMBA/TAM groups.
BFB alone did not cause any changes in the mammary gland structure; typical acini structures were visible. Follicles were found in the deep dermis and acini.
The DMBA group’s tumors were of grade III, which were also seen in DMBA/TAM along with grade II tumors, whereas the DMBA/BFB group’s tumors were just of grade I. In compared to the DMBA and DMBA/TAM groups, BFB reduced mitotic activity by about half, prevented the appearance of any polymorphism, and prevented the creation of any necrotic foci, all of which were observed in the DMBA and DMBA/TAM groups.
The pro-apoptotic activity of BFB was confirmed by BFB treatment to MCF7 where BFB increased both early and late apoptotic cells. The increase in total apoptotic cells was 153-folds. Necrotic cells increased only from 0.1 to 0.2%. to confirm the antimetastatic role of BFB, wound healing assay was done and BFB decreased the migration of MCF7 cells by 29% after 48h.