title: Effects of Pubertal Exposure to Dietary Soy on Estrogen Receptor Activity in the Breast of Cynomolgus Macaques.
abstract: Endogenous estrogens influence mammary gland development during puberty and breast cancer risk during adulthood. Early-life exposure to dietary or environmental estrogens may alter estrogen-mediated processes. Soy foods contain phytoestrogenic isoflavones (IF), which have mixed estrogen agonist/antagonist properties. Here, we evaluated mammary gland responses over time in pubertal female cynomolgus macaques fed diets containing either casein/lactalbumin (n = 12) or soy protein containing a human-equivalent dose of 120 mg IF/day (n = 17) for approximately 4.5 years spanning menarche. We assessed estrogen receptor (ER) expression and activity, promoter methylation of ERs and their downstream targets, and markers of estrogen metabolism. Expression of ERα and classical ERα response genes (TFF1, PGR, and GREB1) decreased with maturity, independent of diet. A significant inverse correlation was observed between TFF1 mRNA and methylation of CpG sites within the TFF1 promoter. Soy effects included lower ERβ expression before menarche and lower mRNA for ERα and GREB1 after menarche. Expression of GATA-3, an epithelial differentiation marker that regulates ERα-mediated transcription, was elevated before menarche and decreased after menarche in soy-fed animals. Soy did not significantly alter expression of other ER activity markers, estrogen-metabolizing enzymes, or promoter methylation for ERs or ER-regulated genes. Our results demonstrate greater ER expression and activity during the pubertal transition, supporting the idea that this life stage is a critical window for phenotypic modulation by estrogenic compounds. Pubertal soy exposure decreases mammary ERα expression after menarche and exerts subtle effects on receptor activity and mammary gland differentiation. Cancer Prev Res; 9(5); 385-95. ©2016 AACR.
authors.affiliation: Department of Pathology, Section on Comparative Medicine, Wake Forest School of Medicine, Winston-Salem, North Carolina. Primate Research Center, Bogor Agricultural University, Bogor, Indonesia. fitriya.dewi@gmail.com fitriya.dewi@cbn.net.id.
authors.forename: Fitriya N
authors.initials: FN
authors.lastname: Dewi
authors.affiliation: Department of Pathology, Section on Comparative Medicine, Wake Forest School of Medicine, Winston-Salem, North Carolina.
authors.forename: Charles E
authors.initials: CE
authors.lastname: Wood
authors.affiliation: Department of Pathology, Section on Comparative Medicine, Wake Forest School of Medicine, Winston-Salem, North Carolina.
authors.forename: Cynthia J
authors.initials: CJ
authors.lastname: Willson
authors.affiliation: Department of Pathology, Section on Comparative Medicine, Wake Forest School of Medicine, Winston-Salem, North Carolina.
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Register
authors.affiliation: Department of Pathology, Section on Comparative Medicine, Wake Forest School of Medicine, Winston-Salem, North Carolina.
authors.forename: Cynthia J
authors.initials: CJ
authors.lastname: Lees
authors.affiliation: Center for Genomics and Personalized Medicine Research, Wake Forest School of Medicine, Winston-Salem, North Carolina.
authors.forename: Timothy D
authors.initials: TD
authors.lastname: Howard
authors.affiliation: Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Duke University School of Medicine, Durham, North Carolina.
authors.forename: Zhiqing
authors.initials: Z
authors.lastname: Huang
authors.affiliation: Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Duke University School of Medicine, Durham, North Carolina.
authors.forename: Susan K
authors.initials: SK
authors.lastname: Murphy
authors.affiliation: Department of Biostatistical Sciences, Wake Forest School of Medicine, Winston-Salem, North Carolina.
authors.forename: Janet A
authors.initials: JA
authors.lastname: Tooze
authors.affiliation: Department of Biostatistical Sciences, Wake Forest School of Medicine, Winston-Salem, North Carolina.
authors.forename: Jeff W
authors.initials: JW
authors.lastname: Chou
authors.affiliation: Department of Cancer Biology, Wake Forest School of Medicine, Winston-Salem, North Carolina.
authors.forename: Lance D
authors.initials: LD
authors.lastname: Miller
authors.affiliation: Department of Pathology, Section on Comparative Medicine, Wake Forest School of Medicine, Winston-Salem, North Carolina.
authors.forename: J Mark
authors.initials: JM
authors.lastname: Cline
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D004032:Diet; D005260:Female; D007150:Immunohistochemistry; D008252:Macaca fascicularis; D008321:Mammary Glands, Animal / Q000187:drug effects* / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D048789:Phytoestrogens / Q000494:pharmacology; D016133:Polymerase Chain Reaction; D011960:Receptors, Estrogen; D012741:Sexual Maturation / Q000187:drug effects*; D030262:Soybean Proteins / Q000494:pharmacology*; D059467:Transcriptome
chemical_list: D048789:Phytoestrogens; D011960:Receptors, Estrogen; D030262:Soybean Proteins