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.
In Specific Aim 1, primary breast stem/progenitor cells will be 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 will 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 DMA methylation, as a result of increased local methyltransferase activities, marks the heritable gene silencing.
In Specific Aim 3, we will 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. In addition, low levels of these methylation changes may exist in normal looking mammary epithelial, leaving a field of cancerization in the human breast. This type of CpG island hypermethylation can be tracked as molecular relics using a mathematical modeling approach developed in our laboratory. We will develop the model further 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 will be provided as a quantitative milestone for this U01 project. These loci are future biomarkers for early breast cancer detection and are putative biosensors to environmental estrogens.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01ES015986-04
Application #
7849065
Study Section
Special Emphasis Panel (ZES1-LKB-E (BR))
Program Officer
Shaughnessy, Daniel
Project Start
2007-08-15
Project End
2011-09-30
Budget Start
2010-06-01
Budget End
2011-09-30
Support Year
4
Fiscal Year
2010
Total Cost
$311,424
Indirect Cost
Name
Ohio State University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
832127323
City
Columbus
State
OH
Country
United States
Zip Code
43210
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Hsu, Pei-Yin; Hsu, Hang-Kai; Singer, Gregory A C et al. (2010) Estrogen-mediated epigenetic repression of large chromosomal regions through DNA looping. Genome Res 20:733-44
Huang, Tim H-M; Esteller, Manel (2010) Chromatin remodeling in mammary gland differentiation and breast tumorigenesis. Cold Spring Harb Perspect Biol 2:a004515
Weng, Yu-I; Hsu, Pei-Yin; Liyanarachchi, Sandya et al. (2010) Epigenetic influences of low-dose bisphenol A in primary human breast epithelial cells. Toxicol Appl Pharmacol 248:111-21
Dworkin, Amy M; Huang, Tim H-M; Toland, Amanda Ewart (2009) Epigenetic alterations in the breast: Implications for breast cancer detection, prognosis and treatment. Semin Cancer Biol 19:165-71

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