title: Impaired mouse mammary gland growth and development is mediated by melatonin and its MT1G protein-coupled receptor via repression of ERα, Akt1, and Stat5.
abstract: To determine whether melatonin, via its MT(1)  G protein-coupled receptor, impacts mouse mammary gland development, we generated a mouse mammary tumor virus (MMTV)-MT1-Flag-mammary gland over-expressing (MT1-mOE) transgenic mouse. Increased expression of the MT(1) -Flag transgene was observed in the mammary glands of pubescent MT1-mOE transgenic female mice, with further significant increases during pregnancy and lactation. Mammary gland whole mounts from MT1-mOE mice showed significant reductions in ductal growth, ductal branching, and terminal end bud formation. Elevated MT(1)  receptor expression in pregnant and lactating female MT1-mOE mice was associated with reduced lobulo-alveolar development, inhibition of mammary epithelial cell proliferation, and significant reductions in body weights of suckling pups. Elevated MT(1)  expression in pregnant and lactating MT1-mOE mice correlated with reduced mammary gland expression of Akt1, phospho-Stat5, Wnt4, estrogen receptor alpha, progesterone receptors A and B, and milk proteins β-casein and whey acidic protein. Estrogen- and progesterone-stimulated mammary gland development was repressed by elevated MT(1)  receptor expression and exogenous melatonin administration. These studies demonstrate that the MT(1)  melatonin receptor and its ligand melatonin play an important regulatory role in mammary gland development and lactation in mice through both growth suppression and alteration of developmental paradigms.
authors.affiliation: Department of Structural and Cellular Biology, Tulane University School of Medicine, New Orleans, LA, USA.
authors.forename: Shulin
authors.initials: S
authors.lastname: Xiang
authors.forename: Lulu
authors.initials: L
authors.lastname: Mao
authors.forename: Lin
authors.initials: L
authors.lastname: Yuan
authors.forename: Tamika
authors.initials: T
authors.lastname: Duplessis
authors.forename: Frank
authors.initials: F
authors.lastname: Jones
authors.forename: Gary W
authors.initials: GW
authors.lastname: Hoyle
authors.forename: Tripp
authors.initials: T
authors.lastname: Frasch
authors.forename: Robert
authors.initials: R
authors.lastname: Dauchy
authors.forename: David E
authors.initials: DE
authors.lastname: Blask
authors.forename: Geetika
authors.initials: G
authors.lastname: Chakravarty
authors.forename: Steven M
authors.initials: SM
authors.lastname: Hill
mesh_terms: D000818:Animals; D047628:Estrogen Receptor alpha / Q000096:biosynthesis / Q000235:genetics; D005260:Female; D007774:Lactation / Q000502:physiology; D008321:Mammary Glands, Animal / Q000187:drug effects / Q000254:growth & development*; D008324:Mammary Tumor Virus, Mouse / Q000235:genetics; D008550:Melatonin / Q000494:pharmacology*; D051379:Mice; D008822:Mice, Transgenic; D011247:Pregnancy; D051057:Proto-Oncogene Proteins c-akt / Q000096:biosynthesis / Q000235:genetics; D044122:Receptor, Melatonin, MT1 / Q000235:genetics / Q000502:physiology*; D050799:STAT5 Transcription Factor / Q000096:biosynthesis / Q000235:genetics
chemical_list: D047628:Estrogen Receptor alpha; D044122:Receptor, Melatonin, MT1; D050799:STAT5 Transcription Factor; C494093:Stat5a protein, mouse; C514862:Akt1 protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D008550:Melatonin