title: Cross-Talk in the Female Rat Mammary Gland: Influence of Aryl Hydrocarbon Receptor on Estrogen Receptor Signaling.
abstract: Cross-talk between the aryl hydrocarbon receptor (AHR) and the estrogen receptor (ER) plays a major role in signaling processes in female reproductive organs.
  
  
  
  We investigated the influence of the AHR ligand 3-methylcholanthrene (3-MC) on ER-mediated signaling in mammary gland tissue of ovariectomized (ovx) rats.
  
  
  
  After 14 days of hormonal decline, ovx rats were treated for 3 days with 4 μg/kg 17β-estradiol (E2), 15 mg/kg 8-prenylnaringenin (8-PN), 15 mg/kg 3-MC, or a combination of these compounds (E2 + 3-MC, 8-PN + 3-MC). Whole-mount preparations of the mammary gland were used to count terminal end buds (TEBs). Protein expression studies (immunohistochemistry, immunofluorescence), a cDNA microarray, pathway analyses, and quantitative real-time polymerase chain reaction (qPCR) were performed to evaluate the interaction between AHR- and ER-mediated signaling pathways.
  
  
  
  E2 treatment increased the number of TEBs and the levels of Ki-67 protein and progesterone receptor (PR); this treatment also changed the expression of 325 genes by more than 1.5-fold. Although 3-MC treatment alone had marginal impact on gene or protein expression, when rats were co-treated with 3-MC and E2, 3-MC strongly inhibited E2-induced TEB development, protein synthesis, and the expression of nearly half of E2-induced genes. This inhibitory effect of 3-MC was partially mirrored when 8-PN was used as an ER ligand. The anti-estrogenicity of ligand-activated AHR was at least partly due to decreased protein levels of ERα in ductal epithelial cells.
  
  
  
  Our data show transcriptome-wide anti-estrogenic properties of ligand-activated AHR on ER-mediated processes in the mammary gland, thereby contributing an explanation for the chemopreventive and endocrine-disrupting potential of AHR ligands.
  
  
  
  Helle J, Bader MI, Keiler AM, Zierau O, Vollmer G, Chittur SV, Tenniswood M, Kretzschmar G. 2016. Cross-talk in the female rat mammary gland: influence of aryl hydrocarbon receptor on estrogen receptor signaling. Environ Health Perspect 124:601-610; http://dx.doi.org/10.1289/ehp.1509680.
authors.affiliation: Institute of Zoology, Molecular Cell Physiology and Endocrinology, Technische Universität Dresden, Dresden, Germany.
authors.forename: Janina
authors.initials: J
authors.lastname: Helle
authors.forename: Manuela I
authors.initials: MI
authors.lastname: Bader
authors.forename: Annekathrin M
authors.initials: AM
authors.lastname: Keiler
authors.forename: Oliver
authors.initials: O
authors.lastname: Zierau
authors.forename: Günter
authors.initials: G
authors.lastname: Vollmer
authors.forename: Sridar V
authors.initials: SV
authors.lastname: Chittur
authors.forename: Martin
authors.initials: M
authors.lastname: Tenniswood
authors.forename: Georg
authors.initials: G
authors.lastname: Kretzschmar
mesh_terms: D000818:Animals; D004958:Estradiol; D047628:Estrogen Receptor alpha; D005260:Female; D008321:Mammary Glands, Animal / Q000378:metabolism*; D051381:Rats; D060888:Real-Time Polymerase Chain Reaction; D018336:Receptors, Aryl Hydrocarbon / Q000378:metabolism*; D011960:Receptors, Estrogen / Q000378:metabolism*; D015398:Signal Transduction; D015533:Transcriptional Activation
chemical_list: D047628:Estrogen Receptor alpha; D018336:Receptors, Aryl Hydrocarbon; D011960:Receptors, Estrogen; D004958:Estradiol