Genetic polymorphisms and protein expression of P53 and BRCA1 in preneoplastic and neoplastic rat mammary glands

Abstract

Breast cancer is the most common type of cancer and the leading cause of cancer-related deaths among women in the United Arab Emirates and worldwide. Although many factors contribute to the high incidence of breast cancer, a considerable number of cases are related to environmental factors. In the present study, breast cancer was induced in female rats using a single dose, 80 mg/kg body wt, of the environmental carcinogen 7,12-dimethylbenz[a]anthracene (DMBA). The aim of the present study, was to characterize some of the molecular changes that occur during breast cancer development in the DMBA-treated rat model. Mammary gland tissues of control and DMBA-treated rats were processed for: i) immunohistochemical probing using anti-BRCA1 antibody to characterize and correlate the localization of this cell cycle protein during progression to cancer, ii) western blotting to analyze the alteration of p53 protein expression in preneoplastic and neoplastic lesions of the mammary glands, and iii) polymerase chain reactions using primers specific for BRCA1 and P53 genes followed by single stranded conformational polymorphism (SSCP) or restriction fragment length polymorphism (RFLP) assays to detect possible mutations in these genes during development of breast cancer. Microscopic examination revealed a wide range of preneoplastic and neoplastic lesions providing a sequence representing the multistep process of breast cancer formation in DMBA-treated rats. Probing for BRCA1 protein revealed a gradual defect in its translocation from the cytoplasm to the nucleus during breast cancer progression. In control rats, BRCA1 was present in the nuclei of terminal duct epithelial cells. However, in the preneoplastic lesions, BRCA1 was localized in both the cytoplasm and nuclei of the epithelial duct cells. In all malignant lesions, BRCA1 was mostly found in the cytoplasm. Western blotting revealed initial downregulation in the expression of p53 protein during breast cancer development. However, with progression towards malignancy, upregulation of p53 was observed. These changes were associated with polymorphism in p53 gene, which was detected in exon 5 using SSCP assay. However, using RFLP and BamHI to digest the PCR products of exon 11 of BRCA1 gene revealed no detectable polymorphisms. In conclusion, molecular characterization of the early changes that occur during development of breast cancer provides some clues for better understanding of its pathogenesis.

Evaluation of associations between TP53 codon 72 polymorphism and onset and progression of oral potentially malignant disorders based on case-control studies

“…Dastjerdi MN 30 reported that TP53 codon 72 polymorphism may be correlated with p53 overexpression and increased risk for colorectal cancer. Al-Dhaheri et al 31 reported that p53 overexpression in the progression towards malignancy of preneoplastic and neoplastic rat mammary glands associated with TP53 polymorphism; while Rybárová et al 32 reported that no statistically signi cant difference was found between TP53 codon 72 polymorphism and p53 protein expression in human breast cancer. These variations in results might be possible due to organ speci city and species differences.…”

Methylnitrosourea, dimethylbenzanthracene and benzoapyrene differentially affect redox pathways, apoptosis and immunity in zebrafish

“…Therefore, P53 expression is a DNA damage biomarker. [35][36][37][38] DMBA exposure in mice stimulated the expression of both p53 and p21WAF1 indicating a DNA injury and in p53-deficient mice, DMBAinduced skin papillomas exerted malignant conversion. 36 In DMBA-induced hamster buccal-pouch carcinogenesis, p53 and iNOS genes were activated in the buccal mucosa.…”

“…36 In DMBA-induced hamster buccal-pouch carcinogenesis, p53 and iNOS genes were activated in the buccal mucosa. 37 The important role of p53 against genomic damage, enhanced genotoxicity of MNU in p53-semideficient state and upregulation of p53 with the progression towards malignancy have been shown in DMBA-induced breast cancer in rats. 38,39 In another study preventive role of green tea extracts has been shown in BaP-induced lung carcinoma in rats, in association with stimulation of p53 levels.…”

Chaperone-mediated autophagy promotes breast cancer angiogenesis via regulation of aerobic glycolysis

“…Breast cancer is the most common cancer and the leading cause of cancer death in women worldwide, many factors contribute to initiation and progression of breast cancer [1,2]. As angiogenesis is essential for tumor growth and metastasis, inhibiting tumor-associated angiogenesis has long been a promising target in limiting cancer progression [3,4].…”