title: Cripto-1 ablation disrupts alveolar development in the mouse mammary gland through a progesterone receptor-mediated pathway.
abstract: Cripto-1, a member of the epidermal growth factor-Cripto-1/FRL-1/Cryptic family, is critical for early embryonic development. Together with its ligand Nodal, Cripto-1 has been found to be associated with the undifferentiated status of mouse and human embryonic stem cells. Several studies have clearly shown that Cripto-1 is involved in regulating branching morphogenesis and epithelial-mesenchymal transition of the mammary gland both in vitro and in vivo and together with the cofactor GRP78 is critical for the maintenance of mammary stem cells ex vivo. Our previous studies showed that mammary-specific overexpression of human Cripto-1 exhibited dramatic morphological alterations in nulliparous mice mammary glands. The present study shows a novel mechanism for Cripto-1 regulation of mammary gland development through direct effects on progesterone receptor expression and pathways regulated by progesterone in the mammary gland. We demonstrate a strict temporal regulation of mouse Cripto-1 (mCripto-1) expression that occurs during mammary gland development and a stage-specific function of mCripto-1 signaling during mammary gland development. Our data suggest that Cripto-1, like the progesterone receptor, is not required for the initial ductal growth but is essential for subsequent side branching and alveologenesis during the initial stages of pregnancy. Dissection of the mechanism by which this occurs indicates that mCripto-1 activates receptor activator NF-κB/receptor activator NF-κB ligand, and NF-κB signaling pathways.
authors.affiliation: Mouse Cancer Genetics Program, National Cancer Institute, National Institutes of Health, Frederick, Maryland.
authors.forename: Malgorzata
authors.initials: M
authors.lastname: Klauzinska
authors.affiliation: Basic Research Laboratory, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
authors.forename: David
authors.initials: D
authors.lastname: McCurdy
authors.affiliation: Mouse Cancer Genetics Program, National Cancer Institute, National Institutes of Health, Frederick, Maryland.
authors.forename: Maria Cristina
authors.initials: MC
authors.lastname: Rangel
authors.affiliation: Basic Research Laboratory, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
authors.forename: Arun
authors.initials: A
authors.lastname: Vaidyanath
authors.affiliation: Mouse Cancer Genetics Program, National Cancer Institute, National Institutes of Health, Frederick, Maryland.
authors.forename: Nadia P
authors.initials: NP
authors.lastname: Castro
authors.affiliation: Departments of Medicine Genetics and Development, Urology, and Systems Biology, Columbia University Medical Center, New York, New York.
authors.forename: Michael M
authors.initials: MM
authors.lastname: Shen
authors.affiliation: Mouse Cancer Genetics Program, National Cancer Institute, National Institutes of Health, Frederick, Maryland.
authors.forename: Monica
authors.initials: M
authors.lastname: Gonzales
authors.affiliation: Mouse Cancer Genetics Program, National Cancer Institute, National Institutes of Health, Frederick, Maryland.
authors.forename: Daniel
authors.initials: D
authors.lastname: Bertolette
authors.affiliation: Mouse Cancer Genetics Program, National Cancer Institute, National Institutes of Health, Frederick, Maryland.
authors.forename: Caterina
authors.initials: C
authors.lastname: Bianco
authors.affiliation: Basic Research Laboratory, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
authors.forename: Robert
authors.initials: R
authors.lastname: Callahan
authors.affiliation: Mouse Cancer Genetics Program, National Cancer Institute, National Institutes of Health, Frederick, Maryland.
authors.forename: David S
authors.initials: DS
authors.lastname: Salomon
authors.affiliation: Basic Research Laboratory, National Cancer Institute, National Institutes of Health, Bethesda, Maryland. Electronic address: raafata@mail.nih.gov.
authors.forename: Ahmed
authors.initials: A
authors.lastname: Raafat
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D000091342:Endoplasmic Reticulum Chaperone BiP; D004815:Epidermal Growth Factor / Q000235:genetics / Q000378:metabolism*; D004847:Epithelial Cells; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D006801:Humans; D008321:Mammary Glands, Animal / Q000166:cytology; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D008954:Models, Biological; D052002:NF-kappa B p50 Subunit / Q000235:genetics / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D009928:Organ Specificity; D011247:Pregnancy; D053245:RANK Ligand / Q000235:genetics / Q000378:metabolism*; D053246:Receptor Activator of Nuclear Factor-kappa B / Q000235:genetics / Q000378:metabolism*; D011980:Receptors, Progesterone / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; C000717248:Hspa5 protein, mouse; D008562:Membrane Glycoproteins; D052002:NF-kappa B p50 Subunit; D009363:Neoplasm Proteins; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D011980:Receptors, Progesterone; C489450:Tdgf1 protein, mouse; C505687:Tnfrsf11a protein, mouse; C505689:Tnfsf11 protein, mouse; C073701:Nfkb1 protein, mouse; D004815:Epidermal Growth Factor