title: Prolactin gene-disruption arrests mammary gland development and retards T-antigen-induced tumor growth.
abstract: Prolactin (PRL), interacting with other hormones from the pituitary, gonad, and placenta, activates specific signals that drive the appropriately timed morphological and functional development of the mammary gland. A mouse model of isolated PRL deficiency (PRL-/-) was created by gene disruption in an effort to further understand the molecular basis of mammary gland development and breast cancer. Whereas primary ductal growth was normal in PRL-/- mice, ductal arborization was minimal (branches/mm2=1.5+/-0.5), and lobular budding was absent. Replacement therapy with PRL injections stimulated a modest degree of lobular budding and ductal arborization (3.75+/-0.9). Pituitary transplants to the kidney capsule of PRL-/- mice restored lobular budding and ductal arborization, to the full extent of that seen in control animals (20. 3+/-5.5). Pregnancy, established by mating progesterone-treated PRL-/- females with PRL-/- males, led to complete morphological development of the mammary gland, appropriate to the gestational stage. PRL treatment stimulated tyrosine phosphorylation and DNA binding activity of Stat5a, but not Stat1 in PRL-/- or PRL+/- females, and Stat5a, but not Stat1, was elevated by estradiol within 24 h. PRL-deficient mice were crossed with mice expressing a dominant oncogene (polyoma middle-T antigen driven by the MMTV promoter, PyVT mice). Palpable (1 mm3) tumors were detected an average of 9 days earlier in hormonally normal females (PRL+/-:PyVT) compared with littermates that were PRL-deficient (PRL-/-:PyVT). The growth rate of PyVT-induced tumors was 30% faster in PRL+/-, than in PRL-/- females.
authors.affiliation: Department of Molecular and Cellular Physiology, University of Cincinnati, Cincinnati, Ohio, OH 45267-0576, USA.
authors.forename: A J
authors.initials: AJ
authors.lastname: Vomachka
authors.forename: S L
authors.initials: SL
authors.lastname: Pratt
authors.forename: J A
authors.initials: JA
authors.lastname: Lockefeer
authors.forename: N D
authors.initials: ND
authors.lastname: Horseman
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000473:pathology; D000818:Animals; D000952:Antigens, Polyomavirus Transforming / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000187:drug effects / Q000378:metabolism; D005260:Female; D008321:Mammary Glands, Animal / Q000187:drug effects / Q000254:growth & development* / Q000378:metabolism; D008325:Mammary Neoplasms, Experimental / Q000235:genetics* / Q000473:pathology*; D051379:Mice; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D008894:Milk Proteins; D010766:Phosphorylation / Q000187:drug effects; D010902:Pituitary Gland / Q000637:transplantation; D011247:Pregnancy; D011388:Prolactin / Q000235:genetics* / Q000378:metabolism / Q000494:pharmacology; D050794:STAT1 Transcription Factor; D050799:STAT5 Transcription Factor; D015534:Trans-Activators / Q000187:drug effects / Q000378:metabolism; D014443:Tyrosine / Q000378:metabolism
chemical_list: D000952:Antigens, Polyomavirus Transforming; D004268:DNA-Binding Proteins; D008894:Milk Proteins; D050794:STAT1 Transcription Factor; D050799:STAT5 Transcription Factor; C494080:Stat1 protein, mouse; C494093:Stat5a protein, mouse; D015534:Trans-Activators; D014443:Tyrosine; D011388:Prolactin