Breast cancer (BCa) is the leading cause of death in women;incidence rates continue to rise globally. Genetic predisposition accounts for less than 15% of BCa risk while main etiological factors are those related to environmental exposure and lifestyle choices. Immigrants to the US from low-risk countries develop a higher BCa risk within one generation. Moreover, risk in the second generation is dependent on whether one is born to mother from homeland or US. The latter finding suggests BCa is of fetal origin. A diet high in fat is likely a major risk factor of BCa in the U.S. Rodent studies showed that the type of fat and the particular critical window of exposure are key determinants of this linkage. The environmental estrogen, Bisphenol A (BPA), found ubiquitously in US populations, is also a suspect. Rats exposed to BPA pre-/peri-natally are more susceptible to DMBA-induced BCa than their unexposed counterparts. Although both BPA and high-fat diets have been separately studied, whether the two, given together, have synergistic action has not been investigated. More importantly, epigenetics, a known mechanism underlying gene by environment interaction, has not been studied in the context of developmental origin of BCa. The investigators recently showed that rats prenatally exposed to high-fat diets (39% of kcal) exhibited a higher DMBA-induced BCa susceptibility than controls exposed to a reference diet (16% of kcal). The high-fat diets also induced marked increases in epithelial cell proliferation along with a unique proliferation gene signature identified by global transcriptome profiling. Using an unbiased methylome profiling technique, the investigators also generated preliminary data in support of epigenetic reprogramming of gene expression in adult mammary glands after prenatal exposure to high-fat diets. Here, they propose the gestational period is a critical developmental window for dietary fatty acids-BPA interaction, that reprograms the mammary methylome, resulting in aberrant gene expression and increased BCa risk in adulthood. Three specific alms are proposed to test this hypothesis and translate findings Into public health action through community outreach:
Aim 1 : To characterize the dose-response of dietary BPA on the developmental effects of high-fat diets on BCa risk in later-life;
Aim 2 : To delineate (a) if the type of fat matters in synergizing with an effective developmental dose of BPA in elevating adult BCa risk, and (b) if a methylome, along with an aberrant mammary epithelial cell proliferative gene signature, is reflective of the combined exposure;
and Aim 3 : To translate research findings into public awareness and action to reduce the burden of adverse lifestyle choices and environmental pollutants on BCa risk through an outreach program that partners with the Pink Ribbon Girls. This study will be the first to examine epigenetics as a mechanism underlying lifestyle choices by environmental toxicant Interaction.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01ES019480-03
Application #
8277984
Study Section
Special Emphasis Panel (ZES1-LKB-V (02))
Program Officer
Reinlib, Leslie J
Project Start
2010-09-22
Project End
2015-05-31
Budget Start
2012-06-01
Budget End
2013-05-31
Support Year
3
Fiscal Year
2012
Total Cost
$420,501
Indirect Cost
$196,990
Name
University of Cincinnati
Department
Public Health & Prev Medicine
Type
Schools of Medicine
DUNS #
041064767
City
Cincinnati
State
OH
Country
United States
Zip Code
45221
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Lam, Hung-Ming; Ho, Shuk-Mei; Chen, Jing et al. (2016) Bisphenol A Disrupts HNF4α-Regulated Gene Networks Linking to Prostate Preneoplasia and Immune Disruption in Noble Rats. Endocrinology 157:207-19
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Govindarajah, Vinothini; Leung, Yuet-Kin; Ying, Jun et al. (2016) In utero exposure of rats to high-fat diets perturbs gene expression profiles and cancer susceptibility of prepubertal mammary glands. J Nutr Biochem 29:73-82
Tam, Neville Ngai-Chung; Zhang, Xiang; Xiao, Hong et al. (2015) Increased susceptibility of estrogen-induced bladder outlet obstruction in a novel mouse model. Lab Invest 95:546-60
Martinez, Alan M; Cheong, Ana; Ying, Jun et al. (2015) Effects of High-Butterfat Diet on Embryo Implantation in Female Rats Exposed to Bisphenol A. Biol Reprod 93:147
Ho, Shuk-Mei; Tam, Neville Ngai Chung (2015) Organoid model shows effect of BPA on prostate development. Nat Rev Urol 12:658-9
Ho, Shuk-Mei; Cheong, Ana; Lam, Hung-Ming et al. (2015) Exposure of Human Prostaspheres to Bisphenol A Epigenetically Regulates SNORD Family Noncoding RNAs via Histone Modification. Endocrinology 156:3984-95
Leung, Yuet-Kin; Chan, Queeny Kwan-Yi; Ng, Chi-Fai et al. (2014) Hsa-miRNA-765 as a key mediator for inhibiting growth, migration and invasion in fulvestrant-treated prostate cancer. PLoS One 9:e98037

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