Transgenerational effects of maternal high fat diet during pregnancy on breast ca

Summary

Principal Investigator: Leena A Hilakivi-Clarke
Abstract: DESCRIPTION (provided by applicant): Maternal exposure to a high fat (HF) diet during pregnancy increases estrogen receptor (ER+) and ER- mammary cancer risk among female offspring in animal models and in humans. The effect may not be limited to F1 generation daughters: we found that an exposure during pregnancy to a diet containing ethinyl estradiol (EE2) increased mammary cancer risk also in granddaughters (F2 generation) and great granddaughters (F3 generation). Since HF diet increases pregnancy E2 levels, we are proposing to investigate in mice whether maternal exposure to HF diet increases the risk of developing ER+ and/or ER- mammary cancer in F1-F4 generation offspring. In addition, we will investigate whether these transgenerational effects involve changes in DNA methylation. Our preliminary analysis performed using massively parallel sequencing identified 144 "named" genes which were either hypo- or hypermethylated in the mammary glands of F1-F3 generation offspring of EE2 exposed dams, compared to controls. 21% of these genes were polycomb target genes (PcGTs), which in turn included some tumor suppressor genes (TSGs), suggesting that maternal diet during pregnancy, including consumption of a HF diet, may induce methylation of PcTGs/TSGs in the offspring's breast. Interestingly, women at high risk of developing breast cancer exhibit methylation of PcGTs and TSGs. The increase in DNA methylation may be caused by up-regulation of DNA methyltransferases (DNMT1, DNMT3a and DNMT3b) and polycombs (EZH2, SUZ12), which we and others have found to occur in the offspring of estrogen exposed dams. Further, up-regulation of DNMTs and polycombs may have been initiated by estrogen-induced suppression of non-coding miRNAs which target them, as seen in MCF-7 human breast cancer cells and mammary glands of rats exposed to EE2 or HF diet in utero (our preliminary data). In this study, we test a hypothesis that maternal exposure to a HF diet during pregnancy induces a transgenerational increase in mammary cancer risk in the F1-F4 generation offspring by inducing DNA methylation of PcTGs/TSGs, via estrogen-induced down-regulation of miRNAs. A causal chain involving estrogen-induced down-regulation of miRNA, up-regulation of DNMTs and polycombs and subsequent methylation of PcGTs/TSGs, leading to increased mammary cancer in F1-F4 generation offspring, will be investigated by treating F1-F4 generation mice with histone deacetylase (HDAC) and DNMT inhibitors. Our preliminary study indicates that an exposure to HDAC+DNMT inhibitors during adult life completely reverses the increase in mammary cancer risk in in utero estrogen exposed mice, but whether these exposures reverse increased DNA methylation and increased mammary tumorigenesis in F2-F4 generations of estrogen exposed dams, is not known. Finally, as there is currently no way of knowing who might have been exposed to high in utero estrogenic environment, we will study whether these individuals can be identified by determining E2/ER regulated miRNA profile in the peripheral blood.
Funding Period: 2012-09-11 - 2016-07-31
more information: NIH RePORT

Top Publications

  1. pmc Exposures to synthetic estrogens at different times during the life, and their effect on breast cancer risk
    Leena Hilakivi-Clarke
    Department of Oncology, Georgetown University, Washington, DC 20057, USA
    J Mammary Gland Biol Neoplasia 18:25-42. 2013
  2. ncbi Exposure to excess estradiol or leptin during pregnancy increases mammary cancer risk and prevents parity-induced protective genomic changes in rats
    Sonia de Assis
    Georgetown University Medical Center, NRB, Room E407, 3970 Reservoir Road, NW, Washington, DC 20057
    Cancer Prev Res (Phila) 6:1194-211. 2013
  3. pmc AISAIC: a software suite for accurate identification of significant aberrations in cancers
    Bai Zhang
    Bradley Department of Electrical and Computer Engineering, Virginia Polytechnic Institute and State University, Arlington, VA 22203, USA, Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA, School of Computer Science and Technology, Xidian University, Xi an 710126, China, Department of Oncology and Department of Gynecology Obstetrics, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC 20007, USA Department of Oncology and Department of Physiology and Biophysics, Georgetown University, Washington, DC 20057, USA and Department of Electrical Engineering and Computer Science, University of Michigan, An Arbor, MI 48109, USA
    Bioinformatics 30:431-3. 2014

Research Grants

  1. Estrogen-T cell Interactions
    Prakash S Nagarkatti; Fiscal Year: 2013
  2. Isothiocyanate-Mediated Breast Cancer Prevention
    Louise R Howe; Fiscal Year: 2013
  3. A MULTILEVEL APPROACH TO ENERGY BALANCE AND CANCER ACROSS THE LIFECOURSE
    Graham A Colditz; Fiscal Year: 2013
  4. Biointeractions of antiestrogens with nitric oxide
    Gregory R J Thatcher; Fiscal Year: 2013
  5. Epigenomics of Bisphenol A Exposure and Disease Risk
    Tim H M Huang; Fiscal Year: 2013
  6. Structural Cell Biology of DNA Repair Machines
    John A Tainer; Fiscal Year: 2013
  7. Signaling and Progression in Prostate Cancer
    Dan Theodorescu; Fiscal Year: 2013
  8. Targeting endocrine resistant breast cancer with anacardic acid
    David Schultz; Fiscal Year: 2013
  9. Center for Systematic Modeling of Cancer Development
    STEPHEN TC WONG; Fiscal Year: 2013
  10. Regulation of miRNA in breast cancer
    Carolyn M Klinge; Fiscal Year: 2013

Detail Information

Publications3

  1. pmc Exposures to synthetic estrogens at different times during the life, and their effect on breast cancer risk
    Leena Hilakivi-Clarke
    Department of Oncology, Georgetown University, Washington, DC 20057, USA
    J Mammary Gland Biol Neoplasia 18:25-42. 2013
    ..New data suggest that these exposures induce epigenetic modifications in the mammary gland and germ cells, thereby causing an inheritable increase in breast cancer risk for multiple generations...
  2. ncbi Exposure to excess estradiol or leptin during pregnancy increases mammary cancer risk and prevents parity-induced protective genomic changes in rats
    Sonia de Assis
    Georgetown University Medical Center, NRB, Room E407, 3970 Reservoir Road, NW, Washington, DC 20057
    Cancer Prev Res (Phila) 6:1194-211. 2013
    ..Specifically, these rats exhibited downregulation of genes involved in differentiation and immune functions and upregulation of genes involved in angiogenesis, growth, and epithelial-to-mesenchymal transition...
  3. pmc AISAIC: a software suite for accurate identification of significant aberrations in cancers
    Bai Zhang
    Bradley Department of Electrical and Computer Engineering, Virginia Polytechnic Institute and State University, Arlington, VA 22203, USA, Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA, School of Computer Science and Technology, Xidian University, Xi an 710126, China, Department of Oncology and Department of Gynecology Obstetrics, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC 20007, USA Department of Oncology and Department of Physiology and Biophysics, Georgetown University, Washington, DC 20057, USA and Department of Electrical Engineering and Computer Science, University of Michigan, An Arbor, MI 48109, USA
    Bioinformatics 30:431-3. 2014
    ..AISAIC also provides users with a parallel computing option to leverage ubiquitous multicore machines...

Research Grants30

  1. Estrogen-T cell Interactions
    Prakash S Nagarkatti; Fiscal Year: 2013
    ..Thus, our studies are aimed at providing insights into the mechanism by which estrogens mediate their toxic effects on the immune system, thereby leading to the development of strategies for their prevention and treatment. ..
  2. Isothiocyanate-Mediated Breast Cancer Prevention
    Louise R Howe; Fiscal Year: 2013
    ..Our proposal is thus highly responsive to several areas of interest defined by PAR-11-079. ..
  3. A MULTILEVEL APPROACH TO ENERGY BALANCE AND CANCER ACROSS THE LIFECOURSE
    Graham A Colditz; Fiscal Year: 2013
    ..To address these aims, we propose four research projects and five cores that form a cohesive, transdisciplinary center focused on research, training/career development, and dissemination. ..
  4. Biointeractions of antiestrogens with nitric oxide
    Gregory R J Thatcher; Fiscal Year: 2013
    ..In Aim 3, the ACI rat, an established model for estrogen-induced mammary carcinogenesis will be used to study the effect of one BT-SERM and NO modulation on carcinogenesis and tumor regression. ..
  5. Epigenomics of Bisphenol A Exposure and Disease Risk
    Tim H M Huang; Fiscal Year: 2013
    ..Epigenomic mapping of these CpG islands may identify potential biomarkers that are used as environmental sensors for monitoring human exposures to environmental estrogens. ..
  6. Structural Cell Biology of DNA Repair Machines
    John A Tainer; Fiscal Year: 2013
    ..abstract_text> ..
  7. Signaling and Progression in Prostate Cancer
    Dan Theodorescu; Fiscal Year: 2013
    ..The long-term objective is to translate our understanding of prostate cancer progression mechanisms into the identification of new drug targets and pre-clinical models that recapitulate key aspects of the human disease. ..
  8. Targeting endocrine resistant breast cancer with anacardic acid
    David Schultz; Fiscal Year: 2013
    ..These studies will provide the first in vivo data regarding the efficacy of AnAc in primary mammary tumor prevention and will establish the serum and tissue levels of AnAc after oral consumption. ..
  9. Center for Systematic Modeling of Cancer Development
    STEPHEN TC WONG; Fiscal Year: 2013
    ..abstract_text> ..
  10. Regulation of miRNA in breast cancer
    Carolyn M Klinge; Fiscal Year: 2013
    ....
  11. Molecular Response and Imaging-based Combination Strategies for Optimal PDT
    Tayyaba Hasan; Fiscal Year: 2013
    ..NMSC on the other hand has many options but the high incidence puts a heavy burden on society in terms of cost and suffering. ..
  12. Significance of PELP1 in Breast Cancer Progression
    VALERIE ANN CORTEZ; Fiscal Year: 2013
    ..abstract_text> ..
  13. Hormones and Tumor Initiating Cells in Human Breast Cancers
    CAROL ANN SARTORIUS; Fiscal Year: 2013
    ..This proposal will also define if chronic use of female hormones increases the number of these tumor initiating cells, and if this explains increased breast cancer incidence with some post-menopausal hormone therapies. ..
  14. Regulation of Genomic Instability in Early Breast Cancer
    Thea D Tlsty; Fiscal Year: 2013
    ..abstract_text> ..
  15. Energy Restrction and Mammary Cancer
    Henry J Thompson; Fiscal Year: 2013
    ....
  16. Identifying mechanisms linking stress biology to human breast cancer
    MARTHA KENT MCCLINTOCK; Fiscal Year: 2013
    ..We predict that completion of these studies will uncover novel stress-induced microenvironment mechanisms affecting mammary tumor growth. ..
  17. INTEGRATIVE PATHOPHYSIOLOGY OF SOLID TUMORS
    Rakesh K Jain; Fiscal Year: 2013
    ..abstract_text> ..
  18. PEDIGREE: Prenatal Environmental Determinants of InterGenerational Risk
    Mary Beth Terry; Fiscal Year: 2013
    ....
  19. The Biology of Prostate Cancer Skeletal Metastases
    EVAN TODD KELLER; Fiscal Year: 2013
    ..This combination of investigators, projects and cores result in a highly synergistic Program that will continue to provide cutting-edge research on PCa bone metastases. ..
  20. Mechanistic Pharmacology of Anti-Mitotics and Apoptosis Regulation
    Timothy J Mitchison; Fiscal Year: 2013
    ..In aim 4 we will pursue several approaches towards translating mechanistic understanding from aims 1-3 into improved patient care. ..