title: Epithelial and non-epithelialPtch1play opposing roles to regulate proliferation and morphogenesis of the mouse mammary gland.
abstract: Patched 1 (Ptch1) has epithelial, stromal and systemic roles in murine mammary gland organogenesis, yet specific functions remain undefined.Cre-recombinase-mediatedPtch1ablation in mammary epithelium increased proliferation and branching, but did not phenocopy transgenic expression of activated smoothened (SmoM2). The epithelium showed no evidence of canonical hedgehog signaling, and hyperproliferation was not blocked by smoothened (SMO) inhibition, suggesting a non-canonical function of PTCH1. Consistent with this possibility, nuclear localization of cyclin B1 was increased. In non-epithelial cells, heterozygousFsp-Cre-mediatedPtch1ablation increased proliferation and branching, with dysplastic terminal end buds (TEB) and ducts. By contrast, homozygousPtch1ablation decreased proliferation and branching, producing stunted ducts filled with luminal cells showing altered ovarian hormone receptor expression. Whole-gland transplantation into wild-type hosts or estrogen/progesterone treatment rescued outgrowth and hormone receptor expression, but not the histological changes. Bone marrow transplantation failed to rescue outgrowth. Ducts ofFsp-Cre;Ptch1fl/flmice were similar toFsp-Cre;SmoM2ducts, butFsp-Cre;SmoM2outgrowths were not stunted, suggesting that the histology might be mediated bySmoin the local stroma, with systemicPtch1required for ductal outgrowth and proper hormone receptor expression in the mammary epithelium.
authors.affiliation: Lester and Sue Smith Breast Center, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.|Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
authors.forename: Teresa
authors.identifier: 0000-0001-6245-7610
authors.initials: T
authors.lastname: Monkkonen
authors.affiliation: Lester and Sue Smith Breast Center, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
authors.forename: John D
authors.initials: JD
authors.lastname: Landua
authors.affiliation: Lester and Sue Smith Breast Center, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.|Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.|Program in Developmental Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
authors.forename: Adriana P
authors.initials: AP
authors.lastname: Visbal
authors.affiliation: Lester and Sue Smith Breast Center, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA mtlewis@bcm.edu.|Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.|Program in Developmental Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
authors.forename: Michael T
authors.identifier: 0000-0002-6330-4007
authors.initials: MT
authors.lastname: Lewis
mesh_terms: D000818:Animals; D016026:Bone Marrow Transplantation; D049109:Cell Proliferation / Q000187:drug effects; D048430:Cell Shape / Q000187:drug effects; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D004848:Epithelium / Q000187:drug effects / Q000378:metabolism*; D004967:Estrogens / Q000494:pharmacology; D005260:Female; D053823:Hedgehog Proteins / Q000378:metabolism; D019426:Integrases / Q000378:metabolism; D008321:Mammary Glands, Animal / Q000166:cytology* / Q000187:drug effects / Q000254:growth & development* / Q000637:transplantation; D051379:Mice; D008954:Models, Biological; D009024:Morphogenesis / Q000187:drug effects; D009154:Mutation / Q000235:genetics; D022423:Myeloid Cells / Q000187:drug effects / Q000378:metabolism; D000072081:Patched-1 Receptor / Q000378:metabolism*; D011374:Progesterone / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D000072086:Smoothened Receptor / Q000378:metabolism
chemical_list: D004967:Estrogens; D053823:Hedgehog Proteins; D000072081:Patched-1 Receptor; C000606240:Ptch1 protein, mouse; C491022:Smo protein, mouse; D000072086:Smoothened Receptor; D011374:Progesterone; C045073:Cre recombinase; D019426:Integrases
keywords: Epithelial-stromal interactions; Hedgehog signaling; Patched-1; Smoothened