title: The Role of Prolactin in Bone Metastasis and Breast Cancer Cell-Mediated Osteoclast Differentiation.
abstract: BACKGROUND
  Metastasis to the bone is a deleterious aspect of breast cancer and is a preferred site that results in bone loss. Hormones such as prolactin (PRL) have not yet been studied for their role in modulating the secondary tumor bone microenvironment.
  
  
  METHODS
  We used quantitative immunohistochemistry with 134 samples of human primary breast cancer and 17 matched primary breast cancers and bone metastases. A Cox proportional hazards regression model was fitted to evaluate the associations between high prolactin receptor (PRLR) expression and time to bone metastasis, adjusting for estrogen receptor status, lymph node status, and chemotherapy status. We assessed osteoclast differentiation, osteoclast size, and measured pit formation in dentine slices. Statistical tests were two-sided.
  
  
  RESULTS
  High PRLR expression in the primary breast tumor was associated with a shorter time to metastasis that includes bone (PRLRAQUA Max-per 100 unit hazard ratio = 1.04, 95% confidence interval = 1.00 to 1.07, P = .03). We observed the PRLR in rare samples of bone metastases and matched primary breast cancer. PRL treatment of breast cancer cells induced osteoclast differentiation and bone lysis via secreted factors and was abrogated by a PRLR antagonist (delta1-9-G129R-hPRL). We demonstrated that sonic hedgehog is a PRL-regulated cytokine in breast cancer cells and part of the mechanism that induces osteoclast differentiation.
  
  
  CONCLUSIONS
  Our evidence indicates that PRL-PRLR can escalate the impact of breast cancer on bone metastasis and that the presence of the PRLR in the tumor microenvironment of breast cancer bone metastasis has the potential to modulate the microenvironment to induce lytic osteoclast formation.
authors.affiliation: Affiliations of authors: University of Calgary, Department of Biological Sciences and Arnie Charbonneau Cancer Institute , Calgary , Canada (AS, AF, YC, LG, CSS); H. Lee Moffitt Cancer Center & Research Institute, Department of Biostatistics and Bioinformatics , Tampa, FL (THJ, JKL); Tom Baker Cancer Centre, Translational Labs , Calgary , Canada (AK, SKP, JH, AC, CE, PAT, DM, AM); Université Paris Descartes, Inserm U1151, Institut Necker Enfants Malades (INEM), Team "Pathophysiology of PRL/GH" , Paris , France (FB, VG); Medical Department of Breast Oncology, The Tumor Hospital of Harbin Medical University , Harbin , China (YC, LC); H. Lee Moffitt Cancer Center & Research Institute, Department of Anatomical Pathology , Tampa, FL (AM).
authors.forename: Ashley
authors.initials: A
authors.lastname: Sutherland
authors.affiliation: Affiliations of authors: University of Calgary, Department of Biological Sciences and Arnie Charbonneau Cancer Institute , Calgary , Canada (AS, AF, YC, LG, CSS); H. Lee Moffitt Cancer Center & Research Institute, Department of Biostatistics and Bioinformatics , Tampa, FL (THJ, JKL); Tom Baker Cancer Centre, Translational Labs , Calgary , Canada (AK, SKP, JH, AC, CE, PAT, DM, AM); Université Paris Descartes, Inserm U1151, Institut Necker Enfants Malades (INEM), Team "Pathophysiology of PRL/GH" , Paris , France (FB, VG); Medical Department of Breast Oncology, The Tumor Hospital of Harbin Medical University , Harbin , China (YC, LC); H. Lee Moffitt Cancer Center & Research Institute, Department of Anatomical Pathology , Tampa, FL (AM).
authors.forename: Amanda
authors.initials: A
authors.lastname: Forsyth
authors.affiliation: Affiliations of authors: University of Calgary, Department of Biological Sciences and Arnie Charbonneau Cancer Institute , Calgary , Canada (AS, AF, YC, LG, CSS); H. Lee Moffitt Cancer Center & Research Institute, Department of Biostatistics and Bioinformatics , Tampa, FL (THJ, JKL); Tom Baker Cancer Centre, Translational Labs , Calgary , Canada (AK, SKP, JH, AC, CE, PAT, DM, AM); Université Paris Descartes, Inserm U1151, Institut Necker Enfants Malades (INEM), Team "Pathophysiology of PRL/GH" , Paris , France (FB, VG); Medical Department of Breast Oncology, The Tumor Hospital of Harbin Medical University , Harbin , China (YC, LC); H. Lee Moffitt Cancer Center & Research Institute, Department of Anatomical Pathology , Tampa, FL (AM).
authors.forename: Yingying
authors.initials: Y
authors.lastname: Cong
authors.affiliation: Affiliations of authors: University of Calgary, Department of Biological Sciences and Arnie Charbonneau Cancer Institute , Calgary , Canada (AS, AF, YC, LG, CSS); H. Lee Moffitt Cancer Center & Research Institute, Department of Biostatistics and Bioinformatics , Tampa, FL (THJ, JKL); Tom Baker Cancer Centre, Translational Labs , Calgary , Canada (AK, SKP, JH, AC, CE, PAT, DM, AM); Université Paris Descartes, Inserm U1151, Institut Necker Enfants Malades (INEM), Team "Pathophysiology of PRL/GH" , Paris , France (FB, VG); Medical Department of Breast Oncology, The Tumor Hospital of Harbin Medical University , Harbin , China (YC, LC); H. Lee Moffitt Cancer Center & Research Institute, Department of Anatomical Pathology , Tampa, FL (AM).
authors.forename: Laurel
authors.initials: L
authors.lastname: Grant
authors.affiliation: Affiliations of authors: University of Calgary, Department of Biological Sciences and Arnie Charbonneau Cancer Institute , Calgary , Canada (AS, AF, YC, LG, CSS); H. Lee Moffitt Cancer Center & Research Institute, Department of Biostatistics and Bioinformatics , Tampa, FL (THJ, JKL); Tom Baker Cancer Centre, Translational Labs , Calgary , Canada (AK, SKP, JH, AC, CE, PAT, DM, AM); Université Paris Descartes, Inserm U1151, Institut Necker Enfants Malades (INEM), Team "Pathophysiology of PRL/GH" , Paris , France (FB, VG); Medical Department of Breast Oncology, The Tumor Hospital of Harbin Medical University , Harbin , China (YC, LC); H. Lee Moffitt Cancer Center & Research Institute, Department of Anatomical Pathology , Tampa, FL (AM).
authors.forename: Tzu-Hua
authors.initials: TH
authors.lastname: Juan
authors.affiliation: Affiliations of authors: University of Calgary, Department of Biological Sciences and Arnie Charbonneau Cancer Institute , Calgary , Canada (AS, AF, YC, LG, CSS); H. Lee Moffitt Cancer Center & Research Institute, Department of Biostatistics and Bioinformatics , Tampa, FL (THJ, JKL); Tom Baker Cancer Centre, Translational Labs , Calgary , Canada (AK, SKP, JH, AC, CE, PAT, DM, AM); Université Paris Descartes, Inserm U1151, Institut Necker Enfants Malades (INEM), Team "Pathophysiology of PRL/GH" , Paris , France (FB, VG); Medical Department of Breast Oncology, The Tumor Hospital of Harbin Medical University , Harbin , China (YC, LC); H. Lee Moffitt Cancer Center & Research Institute, Department of Anatomical Pathology , Tampa, FL (AM).
authors.forename: Jae K
authors.initials: JK
authors.lastname: Lee
authors.affiliation: Affiliations of authors: University of Calgary, Department of Biological Sciences and Arnie Charbonneau Cancer Institute , Calgary , Canada (AS, AF, YC, LG, CSS); H. Lee Moffitt Cancer Center & Research Institute, Department of Biostatistics and Bioinformatics , Tampa, FL (THJ, JKL); Tom Baker Cancer Centre, Translational Labs , Calgary , Canada (AK, SKP, JH, AC, CE, PAT, DM, AM); Université Paris Descartes, Inserm U1151, Institut Necker Enfants Malades (INEM), Team "Pathophysiology of PRL/GH" , Paris , France (FB, VG); Medical Department of Breast Oncology, The Tumor Hospital of Harbin Medical University , Harbin , China (YC, LC); H. Lee Moffitt Cancer Center & Research Institute, Department of Anatomical Pathology , Tampa, FL (AM).
authors.forename: Alexander
authors.initials: A
authors.lastname: Klimowicz
authors.affiliation: Affiliations of authors: University of Calgary, Department of Biological Sciences and Arnie Charbonneau Cancer Institute , Calgary , Canada (AS, AF, YC, LG, CSS); H. Lee Moffitt Cancer Center & Research Institute, Department of Biostatistics and Bioinformatics , Tampa, FL (THJ, JKL); Tom Baker Cancer Centre, Translational Labs , Calgary , Canada (AK, SKP, JH, AC, CE, PAT, DM, AM); Université Paris Descartes, Inserm U1151, Institut Necker Enfants Malades (INEM), Team "Pathophysiology of PRL/GH" , Paris , France (FB, VG); Medical Department of Breast Oncology, The Tumor Hospital of Harbin Medical University , Harbin , China (YC, LC); H. Lee Moffitt Cancer Center & Research Institute, Department of Anatomical Pathology , Tampa, FL (AM).
authors.forename: Stephanie K
authors.initials: SK
authors.lastname: Petrillo
authors.affiliation: Affiliations of authors: University of Calgary, Department of Biological Sciences and Arnie Charbonneau Cancer Institute , Calgary , Canada (AS, AF, YC, LG, CSS); H. Lee Moffitt Cancer Center & Research Institute, Department of Biostatistics and Bioinformatics , Tampa, FL (THJ, JKL); Tom Baker Cancer Centre, Translational Labs , Calgary , Canada (AK, SKP, JH, AC, CE, PAT, DM, AM); Université Paris Descartes, Inserm U1151, Institut Necker Enfants Malades (INEM), Team "Pathophysiology of PRL/GH" , Paris , France (FB, VG); Medical Department of Breast Oncology, The Tumor Hospital of Harbin Medical University , Harbin , China (YC, LC); H. Lee Moffitt Cancer Center & Research Institute, Department of Anatomical Pathology , Tampa, FL (AM).
authors.forename: Jinghui
authors.initials: J
authors.lastname: Hu
authors.affiliation: Affiliations of authors: University of Calgary, Department of Biological Sciences and Arnie Charbonneau Cancer Institute , Calgary , Canada (AS, AF, YC, LG, CSS); H. Lee Moffitt Cancer Center & Research Institute, Department of Biostatistics and Bioinformatics , Tampa, FL (THJ, JKL); Tom Baker Cancer Centre, Translational Labs , Calgary , Canada (AK, SKP, JH, AC, CE, PAT, DM, AM); Université Paris Descartes, Inserm U1151, Institut Necker Enfants Malades (INEM), Team "Pathophysiology of PRL/GH" , Paris , France (FB, VG); Medical Department of Breast Oncology, The Tumor Hospital of Harbin Medical University , Harbin , China (YC, LC); H. Lee Moffitt Cancer Center & Research Institute, Department of Anatomical Pathology , Tampa, FL (AM).
authors.forename: Angela
authors.initials: A
authors.lastname: Chan
authors.affiliation: Affiliations of authors: University of Calgary, Department of Biological Sciences and Arnie Charbonneau Cancer Institute , Calgary , Canada (AS, AF, YC, LG, CSS); H. Lee Moffitt Cancer Center & Research Institute, Department of Biostatistics and Bioinformatics , Tampa, FL (THJ, JKL); Tom Baker Cancer Centre, Translational Labs , Calgary , Canada (AK, SKP, JH, AC, CE, PAT, DM, AM); Université Paris Descartes, Inserm U1151, Institut Necker Enfants Malades (INEM), Team "Pathophysiology of PRL/GH" , Paris , France (FB, VG); Medical Department of Breast Oncology, The Tumor Hospital of Harbin Medical University , Harbin , China (YC, LC); H. Lee Moffitt Cancer Center & Research Institute, Department of Anatomical Pathology , Tampa, FL (AM).
authors.forename: Florence
authors.initials: F
authors.lastname: Boutillon
authors.affiliation: Affiliations of authors: University of Calgary, Department of Biological Sciences and Arnie Charbonneau Cancer Institute , Calgary , Canada (AS, AF, YC, LG, CSS); H. Lee Moffitt Cancer Center & Research Institute, Department of Biostatistics and Bioinformatics , Tampa, FL (THJ, JKL); Tom Baker Cancer Centre, Translational Labs , Calgary , Canada (AK, SKP, JH, AC, CE, PAT, DM, AM); Université Paris Descartes, Inserm U1151, Institut Necker Enfants Malades (INEM), Team "Pathophysiology of PRL/GH" , Paris , France (FB, VG); Medical Department of Breast Oncology, The Tumor Hospital of Harbin Medical University , Harbin , China (YC, LC); H. Lee Moffitt Cancer Center & Research Institute, Department of Anatomical Pathology , Tampa, FL (AM).
authors.forename: Vincent
authors.initials: V
authors.lastname: Goffin
authors.affiliation: Affiliations of authors: University of Calgary, Department of Biological Sciences and Arnie Charbonneau Cancer Institute , Calgary , Canada (AS, AF, YC, LG, CSS); H. Lee Moffitt Cancer Center & Research Institute, Department of Biostatistics and Bioinformatics , Tampa, FL (THJ, JKL); Tom Baker Cancer Centre, Translational Labs , Calgary , Canada (AK, SKP, JH, AC, CE, PAT, DM, AM); Université Paris Descartes, Inserm U1151, Institut Necker Enfants Malades (INEM), Team "Pathophysiology of PRL/GH" , Paris , France (FB, VG); Medical Department of Breast Oncology, The Tumor Hospital of Harbin Medical University , Harbin , China (YC, LC); H. Lee Moffitt Cancer Center & Research Institute, Department of Anatomical Pathology , Tampa, FL (AM).
authors.forename: Cay
authors.initials: C
authors.lastname: Egan
authors.affiliation: Affiliations of authors: University of Calgary, Department of Biological Sciences and Arnie Charbonneau Cancer Institute , Calgary , Canada (AS, AF, YC, LG, CSS); H. Lee Moffitt Cancer Center & Research Institute, Department of Biostatistics and Bioinformatics , Tampa, FL (THJ, JKL); Tom Baker Cancer Centre, Translational Labs , Calgary , Canada (AK, SKP, JH, AC, CE, PAT, DM, AM); Université Paris Descartes, Inserm U1151, Institut Necker Enfants Malades (INEM), Team "Pathophysiology of PRL/GH" , Paris , France (FB, VG); Medical Department of Breast Oncology, The Tumor Hospital of Harbin Medical University , Harbin , China (YC, LC); H. Lee Moffitt Cancer Center & Research Institute, Department of Anatomical Pathology , Tampa, FL (AM).
authors.forename: Patricia A
authors.initials: PA
authors.lastname: Tang
authors.affiliation: Affiliations of authors: University of Calgary, Department of Biological Sciences and Arnie Charbonneau Cancer Institute , Calgary , Canada (AS, AF, YC, LG, CSS); H. Lee Moffitt Cancer Center & Research Institute, Department of Biostatistics and Bioinformatics , Tampa, FL (THJ, JKL); Tom Baker Cancer Centre, Translational Labs , Calgary , Canada (AK, SKP, JH, AC, CE, PAT, DM, AM); Université Paris Descartes, Inserm U1151, Institut Necker Enfants Malades (INEM), Team "Pathophysiology of PRL/GH" , Paris , France (FB, VG); Medical Department of Breast Oncology, The Tumor Hospital of Harbin Medical University , Harbin , China (YC, LC); H. Lee Moffitt Cancer Center & Research Institute, Department of Anatomical Pathology , Tampa, FL (AM).
authors.forename: Li
authors.initials: L
authors.lastname: Cai
authors.affiliation: Affiliations of authors: University of Calgary, Department of Biological Sciences and Arnie Charbonneau Cancer Institute , Calgary , Canada (AS, AF, YC, LG, CSS); H. Lee Moffitt Cancer Center & Research Institute, Department of Biostatistics and Bioinformatics , Tampa, FL (THJ, JKL); Tom Baker Cancer Centre, Translational Labs , Calgary , Canada (AK, SKP, JH, AC, CE, PAT, DM, AM); Université Paris Descartes, Inserm U1151, Institut Necker Enfants Malades (INEM), Team "Pathophysiology of PRL/GH" , Paris , France (FB, VG); Medical Department of Breast Oncology, The Tumor Hospital of Harbin Medical University , Harbin , China (YC, LC); H. Lee Moffitt Cancer Center & Research Institute, Department of Anatomical Pathology , Tampa, FL (AM).
authors.forename: Don
authors.initials: D
authors.lastname: Morris
authors.affiliation: Affiliations of authors: University of Calgary, Department of Biological Sciences and Arnie Charbonneau Cancer Institute , Calgary , Canada (AS, AF, YC, LG, CSS); H. Lee Moffitt Cancer Center & Research Institute, Department of Biostatistics and Bioinformatics , Tampa, FL (THJ, JKL); Tom Baker Cancer Centre, Translational Labs , Calgary , Canada (AK, SKP, JH, AC, CE, PAT, DM, AM); Université Paris Descartes, Inserm U1151, Institut Necker Enfants Malades (INEM), Team "Pathophysiology of PRL/GH" , Paris , France (FB, VG); Medical Department of Breast Oncology, The Tumor Hospital of Harbin Medical University , Harbin , China (YC, LC); H. Lee Moffitt Cancer Center & Research Institute, Department of Anatomical Pathology , Tampa, FL (AM).
authors.forename: Anthony
authors.initials: A
authors.lastname: Magliocco
authors.affiliation: Affiliations of authors: University of Calgary, Department of Biological Sciences and Arnie Charbonneau Cancer Institute , Calgary , Canada (AS, AF, YC, LG, CSS); H. Lee Moffitt Cancer Center & Research Institute, Department of Biostatistics and Bioinformatics , Tampa, FL (THJ, JKL); Tom Baker Cancer Centre, Translational Labs , Calgary , Canada (AK, SKP, JH, AC, CE, PAT, DM, AM); Université Paris Descartes, Inserm U1151, Institut Necker Enfants Malades (INEM), Team "Pathophysiology of PRL/GH" , Paris , France (FB, VG); Medical Department of Breast Oncology, The Tumor Hospital of Harbin Medical University , Harbin , China (YC, LC); H. Lee Moffitt Cancer Center & Research Institute, Department of Anatomical Pathology , Tampa, FL (AM).
authors.forename: Carrie S
authors.initials: CS
authors.lastname: Shemanko
mesh_terms: D000328:Adult; D000368:Aged; D001859:Bone Neoplasms / Q000737:chemistry / Q000378:metabolism* / Q000556:secondary; D001943:Breast Neoplasms / Q000737:chemistry / Q000378:metabolism* / Q000473:pathology; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D053823:Hedgehog Proteins / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D008875:Middle Aged; D009360:Neoplastic Cells, Circulating / Q000737:chemistry; D016017:Odds Ratio; D010010:Osteoclasts / Q000378:metabolism* / Q000473:pathology*; D011388:Prolactin / Q000032:analysis / Q000378:metabolism*; D016016:Proportional Hazards Models; D011981:Receptors, Prolactin / Q000032:analysis / Q000378:metabolism*; D015398:Signal Transduction; D013997:Time Factors; D046888:Tissue Array Analysis
chemical_list: D053823:Hedgehog Proteins; D011981:Receptors, Prolactin; C509239:SHH protein, human; D011388:Prolactin