title: Endocrine control of canine mammary neoplasms: serum reproductive hormone levels and tissue expression of steroid hormone, prolactin and growth hormone receptors.
abstract: BACKGROUND
  Neoplasms of the mammary gland are among the most common diseases in female domestic dogs (Canis familiaris). It is assumed that reproductive hormones influence tumorigenesis in this species, although the precise role of the endocrine milieu and reproductive state is subject to continuing discussion. In line with this, a recent systematic review of available data on the development of mammary neoplasms revealed weak evidence for risk reduction after neutering and an effect of age at neutering. Investigation of several hormone receptors has revealed decreased expression of estrogen receptor-alpha (ERα, ESR1), progesterone (P4) receptor (PGR), prolactin (PRL) receptor (PRLR) and growth hormone receptor (GHR) associated with neoplastic differentiation of mammary tissues. In other studies, increased levels of estrogens, progesterone and prolactin were found in serum and/or tissue homogenates of dogs with malignant neoplasms. However, the association between these entities within one animal population was never previously examined. Therefore, this study investigated the association between circulating serum concentrations of estradiol-17β, progesterone and prolactin, and gene expression of ERα (ESR1), ERβ (ESR2), PGR, PRLR, PRL and GHR, with respect to reproductive state (spayed vs. intact) and cycle stage (anestrus vs. diestrus). Additionally, the expression of E-cadherin (CDH-1) was evaluated as a possible indicator of metastatic potential.
  
  
  RESULTS
  For all receptors, the lowest gene expression was found in malignant tumors compared to normal tissues of affected dogs. Steroid levels were not influenced by their corresponding receptor expression in mammary neoplasms, but increased PRL levels were negatively associated with low PRLR gene expression in malignant tumors. The expression of CDH-1 was influenced by tumor malignancy and cycle stage, i.e., the highest gene expression was found in benign mammary tumors in diestrous dogs compared to normal and malignant mammary tissues of anestrous and spayed dogs.
  
  
  CONCLUSIONS
  Herein, it has been confirmed that transformation towards malignant neoplasms is associated with significant reduction of gene expression of particular hormone receptors. Only PRLR in malignant tumors seems to be influenced by circulating PRL levels. In dogs, CDH-1 can be used as a prognostic factor; its expression, however, in benign tumors is influenced by cycle stage.
authors.affiliation: Clinic of Reproductive Medicine, Vetsuisse Faculty University of Zurich, Winterthurerstrasse 260, Zurich, 8057, Switzerland. mspoerri@vetclinics.uzh.ch.|Institute of Veterinary Anatomy, Vetsuisse Faculty University of Zurich, Winterthurerstrasse 260, Zurich, 8057, Switzerland. mspoerri@vetclinics.uzh.ch.
authors.forename: Michèle
authors.initials: M
authors.lastname: Spoerri
authors.affiliation: Institute of Veterinary Pathology, Vetsuisse Faculty University of Zurich, Winterthurerstrasse 268/272, Zurich, 8057, Switzerland. franco.guscetti@vetpath.uzh.ch.
authors.forename: Franco
authors.initials: F
authors.lastname: Guscetti
authors.affiliation: Section of Epidemiology, Vetsuisse Faculty, Winterthurerstrasse 270, Zurich, 8057, Switzerland. sonja.hartnack@access.uzh.ch.
authors.forename: Sonja
authors.initials: S
authors.lastname: Hartnack
authors.affiliation: Institute of Veterinary Anatomy, Vetsuisse Faculty University of Zurich, Winterthurerstrasse 260, Zurich, 8057, Switzerland. boosa@vetanat.uzh.ch.
authors.forename: Alois
authors.initials: A
authors.lastname: Boos
authors.affiliation: Department of Animal Health, Faculty of Veterinary Medicine, Utrecht University, P.O Box 80125, Utrecht, 3508 TC, The Netherlands. C.H.Y.Oei@uu.nl.
authors.forename: Christine
authors.initials: C
authors.lastname: Oei
authors.affiliation: Clinic of Reproductive Medicine, Vetsuisse Faculty University of Zurich, Winterthurerstrasse 260, Zurich, 8057, Switzerland. obalogh@vetclinics.uzh.ch.
authors.forename: Orsolya
authors.initials: O
authors.lastname: Balogh
authors.affiliation: Division of Animal Anatomy, Department of Animal Physiology and Biostructure, Faculty of Veterinary Medicine, Wroclaw University of Environmental and Life Sciences, Wroclaw, Poland. renatanowaczyk@o2.pl.
authors.forename: Renata M
authors.initials: RM
authors.lastname: Nowaczyk
authors.affiliation: Clinic of Reproductive Medicine, Vetsuisse Faculty University of Zurich, Winterthurerstrasse 260, Zurich, 8057, Switzerland. erikamichel@bluewin.ch.
authors.forename: Erika
authors.initials: E
authors.lastname: Michel
authors.affiliation: Clinic of Reproductive Medicine, Vetsuisse Faculty University of Zurich, Winterthurerstrasse 260, Zurich, 8057, Switzerland. ireichler@vetclinics.uzh.ch.
authors.forename: Iris M
authors.initials: IM
authors.lastname: Reichler
authors.affiliation: Institute of Veterinary Anatomy, Vetsuisse Faculty University of Zurich, Winterthurerstrasse 260, Zurich, 8057, Switzerland. kowalewski@vetanat.uzh.ch.
authors.forename: Mariusz P
authors.initials: MP
authors.lastname: Kowalewski
mesh_terms: D000818:Animals; D004283:Dog Diseases / Q000378:metabolism*; D004285:Dogs; D004967:Estrogens / Q000097:blood / Q000378:metabolism; D030762:Estrous Cycle; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D007044:Hysterectomy; D015674:Mammary Neoplasms, Animal / Q000378:metabolism*; D011372:Progestins / Q000097:blood / Q000378:metabolism; D011388:Prolactin / Q000378:metabolism; D011981:Receptors, Prolactin / Q000235:genetics / Q000378:metabolism*; D011986:Receptors, Somatotropin / Q000235:genetics / Q000378:metabolism*; D011987:Receptors, Steroid / Q000235:genetics / Q000378:metabolism*
chemical_list: D004967:Estrogens; D011372:Progestins; D011981:Receptors, Prolactin; D011986:Receptors, Somatotropin; D011987:Receptors, Steroid; D011388:Prolactin