Genetic Reprogramming of Human Mammary Cells by Environmental Carcinogens Released into Breast Milk

Abstract

Epidemiologic studies indicate that high serum levels of chlorinated pollutants such as dioxins or pesticides constitute a risk factor for breast cancer in postmenopausal women. This finding has been attributed to the ability of organochlorine compounds to induce the expression of cytochrome P450 (CYP) enzymes, which are thought to increase the burden of genotoxic metabolites. However, it was not clear whether the incriminated pollutants accumulate to sufficiently high levels within the human body to be able to promote significant transcriptional responses. Here, milk samples from nursing mothers were processed by gel permeation chromatography to isolate complex mixtures of residues containing both endogenous hormones and lipophilic contaminants of environmental origin. High-density oligonucleotide microarrays were used to monitor global transcriptional profiles in a human cell line (MCF7) that represents one of the most frequently used model systems to study breast cancer biology. We found that all breast milk extracts were able to reprogram the genome of MCF7 cells by imposing a typically estrogenic expression fingerprint. This estrogenic background was overlapped only by the induction of transcripts coding for CYP1A1 and, to a minor degree, CYP1B1. The magnitude of induction of these metabolic enzymes correlated with the respective organochlorine concentrations. Thus, in support of previous epidemiologic studies, we demonstrate that contaminants released from human adipose tissue trigger a potentially genotoxic pathway in cells from the mammary gland.