title: Deficiency of X-Linked Protein Kinase Nrk during Pregnancy Triggers Breast Tumor in Mice.
abstract: The onset and/or growth of breast tumor are controlled, at least in part, by estrogen. Therefore, to prevent the development of breast tumor, estrogen-dependent proliferation of mammary epithelial cells during pregnancy needs to be suppressed once the mammary gland is fully developed to enable lactation. However, the underlying molecular mechanisms remain unknown. Nrk is an X-linked protein serine/threonine kinase in the germinal center kinase family. Herein, we demonstrate a frequent occurrence of breast tumors in homozygous and heterozygous Nrk mutant mice that have experienced pregnancy/parturition. The tumors never developed in the mutant mice without a history of pregnancy/parturition. They exhibited histopathological features of noninvasive tubular adenocarcinoma, and expressed estrogen receptor α. At late gestation when estrogen receptor α expression was significantly reduced in the wild-type mammary gland, grossly normal mammary glands in the pregnant Nrk mutant mice occasionally contained hyperplastic foci continuously expressing the receptor. Consistently, Nrk expression was induced in the wild-type mammary gland at this period of pregnancy. On the other hand, the pregnant Nrk mutant mice also showed elevated blood estrogen levels at late gestation. We suggest that Nrk suppresses the excessive proliferation of mammary epithelial cells during pregnancy, and the impairment of this regulatory system leads to frequent occurrence of breast tumor in Nrk mutant mice.
authors.affiliation: Department of Biological Sciences, Tokyo Institute of Technology, Yokohama, Japan; Center for Matrix Biology and Medicine, Graduate School of Medicine, Tokai University, Isehara, Japan; Department of Regenerative Medicine, Tokai University School of Medicine, Isehara, Japan.
authors.forename: Takayo
authors.initials: T
authors.lastname: Yanagawa
authors.affiliation: Department of Biological Sciences, Tokyo Institute of Technology, Yokohama, Japan.
authors.forename: Kimitoshi
authors.initials: K
authors.lastname: Denda
authors.affiliation: Department of Biological Sciences, Tokyo Institute of Technology, Yokohama, Japan.
authors.forename: Takuya
authors.initials: T
authors.lastname: Inatani
authors.affiliation: Department of Biological Sciences, Tokyo Institute of Technology, Yokohama, Japan; Cell Biology Unit, Institute of Innovative Research, Tokyo Institute of Technology, Yokohama, Japan.
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Fukushima
authors.affiliation: Department of Biological Sciences, Tokyo Institute of Technology, Yokohama, Japan.
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Tanaka
authors.affiliation: Department of Pathology, Tokai University School of Medicine, Isehara, Japan.
authors.forename: Nobue
authors.initials: N
authors.lastname: Kumaki
authors.affiliation: Center for Matrix Biology and Medicine, Graduate School of Medicine, Tokai University, Isehara, Japan; Department of Regenerative Medicine, Tokai University School of Medicine, Isehara, Japan.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Inagaki
authors.affiliation: Department of Biological Sciences, Tokyo Institute of Technology, Yokohama, Japan; Cell Biology Unit, Institute of Innovative Research, Tokyo Institute of Technology, Yokohama, Japan. Electronic address: makomada@bio.titech.ac.jp.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Komada
mesh_terms: D000818:Animals; D001940:Breast / Q000378:metabolism / Q000473:pathology; D001943:Breast Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D015536:Down-Regulation; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism; D004967:Estrogens / Q000097:blood; D005260:Female; D050172:Genes, X-Linked / Q000235:genetics; D000081410:Germinal Center Kinases; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D007774:Lactation; D061986:MCF-7 Cells; D008297:Male; D008325:Mammary Neoplasms, Experimental / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D011247:Pregnancy; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism
chemical_list: D047628:Estrogen Receptor alpha; D004967:Estrogens; D000081410:Germinal Center Kinases; D047908:Intracellular Signaling Peptides and Proteins; C411848:Nik related kinase; D017346:Protein Serine-Threonine Kinases