Cripto-1 Ablation Disrupts Alveolar Development in the Mouse Mammary Gland through a Progesterone Receptor–Mediated Pathway

• Published in: The American journal of pathology Vol. 185; no. 11; pp. 2907 - 2922
• Main Authors: Klauzinska, Malgorzata, McCurdy, David, Rangel, Maria Cristina, Vaidyanath, Arun, Castro, Nadia P, Shen, Michael M, Gonzales, Monica, Bertolette, Daniel, Bianco, Caterina, Callahan, Robert, Salomon, David S, Raafat, Ahmed
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.11.2015; American Society for Investigative Pathology
• Subjects: Animals; Cell Proliferation; Epidermal Growth Factor - genetics; Epidermal Growth Factor - metabolism; Epithelial Cells; Epithelial-Mesenchymal Transition; Female; Humans; Mammary Glands, Animal - cytology; Membrane Glycoproteins - genetics; Membrane Glycoproteins - metabolism; Mice; Mice, Inbred BALB C; Mice, Knockout; Models, Biological; Neoplasm Proteins - genetics; Neoplasm Proteins - metabolism; NF-kappa B p50 Subunit - genetics; NF-kappa B p50 Subunit - metabolism; Organ Specificity; Pathology; Pregnancy; RANK Ligand - genetics; RANK Ligand - metabolism; Receptor Activator of Nuclear Factor-kappa B - genetics; Receptor Activator of Nuclear Factor-kappa B - metabolism; Receptors, Progesterone - genetics; Receptors, Progesterone - metabolism; Regular; Signal Transduction
• ISSN: 0002-9440; 1525-2191
• DOI: 10.1016/j.ajpath.2015.07.023

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.