title: Estrogen modulates mesenchyme-epidermis interactions in the adult nipple.
abstract: Maintenance of specialized epidermis requires signals from the underlying mesenchyme; however, the specific pathways involved remain to be identified. By recombining cells from the ventral skin of theK14-PTHrPtransgenic mice [which overexpress parathyroid hormone-related protein (PTHrP) in their developing epidermis and mammary glands] with those from wild type, we show that transgenic stroma is sufficient to reprogram wild-type keratinocytes into nipple-like epidermis. To identify candidate nipple-specific signaling factors, we compared gene expression signatures of sorted Pdgfrα-positive ventralK14-PTHrPand wild-type fibroblasts, identifying differentially expressed transcripts that are involved in WNT, HGF, TGFβ, IGF, BMP, FGF and estrogen signaling. Considering that some of the growth factor pathways are targets for estrogen regulation, we examined the upstream role of this hormone in maintaining the nipple. Ablation of estrogen signaling through ovariectomy produced nipples with abnormally thin epidermis, and we identified TGFβ as a negatively regulated target of estrogen signaling. Estrogen treatment represses Tgfβ1 at the transcript and protein levels inK14-PTHrPfibroblastsin vitro, while ovariectomy increasesTgfb1levels inK14-PTHrPventral skin. Moreover, ectopic delivery of Tgfβ1 protein into nipple connective tissue reduced epidermal proliferation. Taken together, these results show that specialized nipple epidermis is maintained by estrogen-induced repression of TGFβ signaling in the local fibroblasts.
authors.affiliation: Medical Sciences Program, Indiana University School of Medicine, Bloomington, IN 47405, USA.
authors.forename: Hsing-Jung
authors.initials: HJ
authors.lastname: Wu
authors.affiliation: Department of Developmental and Cell Biology, Sue and Bill Gross Stem Cell Research Center, Center for Complex Biological Systems, University of California Irvine, Irvine, CA 92697, USA.|Department of Anatomy, School of Medicine, Kyungpook National University, Daegu, 41944, Korea.|Biomedical Research Institute, Kyungpook National University Hospital, Daegu, 41944, Korea.
authors.forename: Ji Won
authors.initials: JW
authors.lastname: Oh
authors.affiliation: Department of Dermatology, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
authors.forename: Dan F
authors.initials: DF
authors.lastname: Spandau
authors.affiliation: Department of Surgery, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
authors.forename: Sunil
authors.initials: S
authors.lastname: Tholpady
authors.affiliation: Medical Sciences Program, Indiana University School of Medicine, Bloomington, IN 47405, USA.
authors.forename: Jesus
authors.initials: J
authors.lastname: Diaz
authors.affiliation: Medical Sciences Program, Indiana University School of Medicine, Bloomington, IN 47405, USA.
authors.forename: Laura J
authors.initials: LJ
authors.lastname: Schroeder
authors.affiliation: Medical Sciences Program, Indiana University School of Medicine, Bloomington, IN 47405, USA.
authors.forename: Carlos D
authors.initials: CD
authors.lastname: Offutt
authors.affiliation: Department of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, PA 16802, USA.
authors.forename: Adam B
authors.initials: AB
authors.lastname: Glick
authors.affiliation: Department of Developmental and Cell Biology, Sue and Bill Gross Stem Cell Research Center, Center for Complex Biological Systems, University of California Irvine, Irvine, CA 92697, USA.
authors.forename: Maksim V
authors.initials: MV
authors.lastname: Plikus
authors.affiliation: Medical Sciences Program, Indiana University School of Medicine, Bloomington, IN 47405, USA.
authors.forename: Sachiko
authors.initials: S
authors.lastname: Koyama
authors.affiliation: Medical Sciences Program, Indiana University School of Medicine, Bloomington, IN 47405, USA jgfoley@indiana.edu.|Department of Dermatology, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
authors.forename: John
authors.identifier: 0000-0003-0266-8488
authors.initials: J
authors.lastname: Foley
mesh_terms: D000375:Aging / Q000502:physiology*; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D002450:Cell Communication / Q000187:drug effects*; D065150:Cellular Reprogramming; D003094:Collagen / Q000378:metabolism; D019295:Computational Biology; D020405:Dermis / Q000166:cytology; D015536:Down-Regulation / Q000235:genetics; D000078404:Epidermal Cells; D004967:Estrogens / Q000494:pharmacology*; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D015603:Keratinocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008648:Mesoderm / Q000166:cytology*; D008810:Mice, Inbred C57BL; D009558:Nipples / Q000166:cytology*; D020411:Oligonucleotide Array Sequence Analysis; D010053:Ovary / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000378:metabolism; D011960:Receptors, Estrogen / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: D015415:Biomarkers; D004967:Estrogens; D012333:RNA, Messenger; D011960:Receptors, Estrogen; D016212:Transforming Growth Factor beta; D003094:Collagen; D020796:Receptor, Platelet-Derived Growth Factor alpha
keywords: Epidermis; Estrogen receptor α; Fibroblast; Nipple; TGFβ