Organophosphorous pesticides and estrogen induce transformation of breast cells affecting p53 and c-Ha-ras genes

Abstract

Cancer progression has been associated with an increase in genomic instability indicated by inactivation of tumor suppressor genes and activation of oncogenes. Epidemiological and experimental evidence has implicated estrogens in the etiology of breast cancer. To study environmental organophosphorous pesticides is of interest since evidence indicate that pesticides may enhance cell division, increasing the risk of breast cancer. The aim was to evaluate the effects of these pesticides, such as parathion and malathion in the presence of estrogen on malignant transformation as well as on genomic instability, that is in the frequency of loss of heterozygosity (LOH) and microsatellite instability (MSI). The MCF-10F immortalized human breast epithelial cell line, that was treated with parathion or malathion alone and in combination with estrogen was used. These studies indicated that either pesticide alone or in combination with estrogen induced malignant transformation as shown by anchorage-independent growth capability and invasive characteristics in comparison to control. Such malignant phenotypic characteristics were corroborated by significant (P<0.05) increase in p53 and c-Ha-ras protein expression. Results indicated different degrees of allelic imbalance in the form of LOH or MSI with different microsatellite markers. MSI was found in malathion and estrogen-treated cells with a marker used for p53 tumor suppressor gene at loci 17p13.1. The same combination of substances presented MSI with a marker used for c-Ha-ras mapped in chromosome 11p14.1, as well as mutations in c-Ha-ras for codons 12 and 61. LOH was observed in codon 12 in the presence of estrogen or malathion alone. Parathion alone and combined with estrogen induced MSI in codon 61. It can be concluded that the organophosphorous pesticides parathion and malathion induced malignant transformation of breast cells through genomic instability altering p53 and c-Ha-ras, considered pivotal to cancer process.