Ohio State University
Environmental Epigenetics and Stem/Progenitor Cell Injury
Tim H.M. Huang
Environmental exposure to endocrine-disrupting agents, or xenoestrogens, can increase the risk of developing breast cancer. Animal and population studies suggest an imprinting phenomenon whereby early exposure of xenoestrogen can lead to tumorigenesis later in life. The molecular mechanism by which these environmental stressors can transform breast genomes is not well understood.
Our preliminary data prompt us to hypothesize that epigenetic alteration, in the form of CpG island hypermethylation, transmits this imprinted information to the progeny of undifferentiated cells pre-exposed to xenoestrogens. Specifically, we propose that immature cells located in the stem/progenitor compartment of the human breast are prime targets of this environmental insult. Our research has been carried out under three major aims.
- In Specific Aim 1, primary breast stem/progenitor cells are exposed to xenoestrogens - diethylstilbestrol, bisphenol A, or 17(3-estradiol in an in vitro system. 'Global analysis is expected to identify altered methylation status in 1-2% of ~29,000 CpG islands analyzed. These epigenetic events can be the direct results of exposing stem/progenitor cells to xenoestrogens. The epigenetic memory of this injury is then transmitted to differentiated epithelial cells and in turn leads to breast tumorigenesis in a xenograft model.
- In Specific Aim 2, we functionally determine whether the prolonged exposure of these endocrine chemicals to stem/progenitor cells disrupt the homeostasis of estrogen signaling and triggers an epigenetic cascade in its downstream targets. Polycomb repressors can be recruited to promoter CpG islands followed by the addition of DNA methyltransferases at these promoters. Acquired DNA methylation, as a result of increased local methyltransferase activities, marks the heritable gene silencing.
- In Specific Aim 3, we demonstrate that CpG island hypermethylation induced by xenoestrogen exposure is also observed in clinical samples. The presence of these molecular alterations in primary breast tumors may constitute a xenoestrogen epigenotype(s). In this regard, patients exhibiting this epigenotype are likely exposed to xenoestrogens in their early lives.
Low levels of these methylation changes may also occur in normal looking mammary epithelial cells, leaving a field of cancer-susceptibility in the human breast. This type of CpG island hypermethylation can be tracked as a molecular relic using a mathematical modeling approach developed in our laboratory. We are working on a model to recreate the history of xenoestrogen- induced breast tumorigenesis, from pre-neoplastic lesions to hyperplasia to carcinoma in situ to invasive carcinoma. Clinical sensitivity and specificity of potential CpG island loci pinpointing the xenoestrogen epigenotype have been a quantitative milestone for this project. These loci are future biomarkers for early breast cancer detection and are putative biosensors to environmental estrogens.