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.
In this study, we will determine whether maternal exposure to a high fat diet during pregnancy, which elevates maternal estradiol levels, increases mammary cancer risk in F1-F4 generation mouse offspring by inducing methylation of PcGTs/TSGs. We also will determine whether increased methylation is associated with suppression of miRNAs which target DNA methyltransferases and polycombs. Finally, we will determine whether suppression of miRNAs in the peripheral RNA serves as a marker of having been exposed to elevated estrogenic environment in utero.
|Shi, Xu; Wang, Xiao; Wang, Tian-Li et al. (2018) SparseIso: a novel Bayesian approach to identify alternatively spliced isoforms from RNA-seq data. Bioinformatics 34:56-63|
|Chen, Xi; Shi, Xu; Hilakivi-Clarke, Leena et al. (2017) PSSV: a novel pattern-based probabilistic approach for somatic structural variation identification. Bioinformatics 33:177-183|
|Zhang, Xiyuan; Cook, Katherine L; Warri, Anni et al. (2017) Lifetime Genistein Intake Increases the Response of Mammary Tumors to Tamoxifen in Rats. Clin Cancer Res 23:814-824|
|Nguyen, Nguyen M; de Oliveira Andrade, Fabia; Jin, Lu et al. (2017) Maternal intake of high n-6 polyunsaturated fatty acid diet during pregnancy causes transgenerational increase in mammary cancer risk in mice. Breast Cancer Res 19:77|
|Wang, Xiao; Gu, Jinghua; Hilakivi-Clarke, Leena et al. (2017) DM-BLD: differential methylation detection using a hierarchical Bayesian model exploiting local dependency. Bioinformatics 33:161-168|
|Sumis, Allison; Cook, Katherine L; Andrade, Fabia O et al. (2016) Social isolation induces autophagy in the mouse mammary gland: link to increased mammary cancer risk. Endocr Relat Cancer 23:839-56|
|Chen, Xi; Jung, Jin-Gyoung; Shajahan-Haq, Ayesha N et al. (2016) ChIP-BIT: Bayesian inference of target genes using a novel joint probabilistic model of ChIP-seq profiles. Nucleic Acids Res 44:e65|
|Cook, Katherine L; Soto-Pantoja, David R; Clarke, Pamela A G et al. (2016) Endoplasmic Reticulum Stress Protein GRP78 Modulates Lipid Metabolism to Control Drug Sensitivity and Antitumor Immunity in Breast Cancer. Cancer Res 76:5657-5670|
|Fontelles, Camile Castilho; Guido, Luiza Nicolosi; Rosim, Mariana Papaléo et al. (2016) Paternal programming of breast cancer risk in daughters in a rat model: opposing effects of animal- and plant-based high-fat diets. Breast Cancer Res 18:71|
|Fontelles, Camile Castilho; Carney, Elissa; Clarke, Johan et al. (2016) Paternal overweight is associated with increased breast cancer risk in daughters in a mouse model. Sci Rep 6:28602|
Showing the most recent 10 out of 27 publications