title: Circulating and disseminated tumor cells from breast cancer patient-derived xenograft-bearing mice as a novel model to study metastasis.
abstract: BACKGROUND
  Real-time monitoring of biologic changes in tumors may be possible by investigating the transitional cells such as circulating tumor cells (CTCs) and disseminated tumor cells in bone marrow (BM-DTCs). However, the small numbers of CTCs and the limited access to bone marrow aspirates in cancer patients pose major hurdles. The goal of this study was to determine whether breast cancer (BC) patient-derived xenograft (PDX) mice could provide a constant and renewable source of CTCs and BM-DTCs, thereby representing a unique system for the study of metastatic processes.
  
  
  METHODS
  CTCs and BM-DTCs, isolated from BC PDX-bearing mice, were identified by immunostaining for human pan-cytokeratin and nuclear counterstaining of red blood cell-lysed blood and bone marrow fractions, respectively. The rate of lung metastases (LM) was previously reported in these lines. Associations between the presence of CTCs, BM-DTCs, and LM were assessed by the Fisher's Exact and Cochran-Mantel-Haenszel tests. Two separate genetic signatures associated with the presence of CTC clusters and with lung metastatic potential were computed by using the expression arrays of primary tumors from different PDX lines and subsequently overlapped to identify common genes.
  
  
  RESULTS
  In total, 18 BC PDX lines were evaluated. CTCs and BM-DTCs, present as either single cells or clusters, were detected in 83% (15 of 18) and 62.5% (10 to16) of the lines, respectively. A positive association was noted between the presence of CTCs and BM-DTCs within the same mice. LM was previously found in 9 of 18 (50%) lines, of which all nine had detectable CTCs. The presence of LM was strongly associated with the detection of CTC clusters but not with individual cells or detection of BM-DTCs. Overlapping of the two genetic signatures of the primary PDX tumors associated with the presence of CTC clusters and with lung metastatic potential identified four genes (HLA-DP1A, GJA1, PEG3, and XIST). This four-gene profile predicted distant metastases-free survival in publicly available datasets of early BC patients.
  
  
  CONCLUSIONS
  This study suggests that CTCs and BM-DTCs detected in BC PDX-bearing mice may represent a valuable and unique preclinical model for investigating the role of these rare cells in tumor metastases.
authors.affiliation: Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX, USA. m.giuliano@unina.it.|Department of Clinical Medicine and Surgery, University Federico II, Naples, Italy. m.giuliano@unina.it.
authors.forename: Mario
authors.initials: M
authors.lastname: Giuliano
authors.affiliation: Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX, USA. sabrinah@bcm.edu.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Herrera
authors.affiliation: Department of Pharmacy Practice and Translational Research, University of Houston, Houston, TX, USA. pichristiny@me.com.
authors.forename: Pavel
authors.initials: P
authors.lastname: Christiny
authors.affiliation: Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX, USA. cashaw@bcm.edu.|Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA. cashaw@bcm.edu.
authors.forename: Chad
authors.initials: C
authors.lastname: Shaw
authors.affiliation: Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX, USA. creighto@bcm.edu.|Department of Medicine, Baylor College of Medicine, Houston, TX, USA. creighto@bcm.edu.
authors.forename: Chad J
authors.initials: CJ
authors.lastname: Creighton
authors.affiliation: Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX, USA. tmitchel@bcm.edu.
authors.forename: Tamika
authors.initials: T
authors.lastname: Mitchell
authors.affiliation: Department of Pharmacy Practice and Translational Research, University of Houston, Houston, TX, USA. rrbhat2@central.uh.edu.
authors.forename: Raksha
authors.initials: R
authors.lastname: Bhat
authors.affiliation: Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX, USA. xiaomeiz@bcm.edu.
authors.forename: Xiaomei
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX, USA. smao@bcm.edu.
authors.forename: Sufeng
authors.initials: S
authors.lastname: Mao
authors.affiliation: Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX, USA. dobrolec@bcm.edu.
authors.forename: Lacey E
authors.initials: LE
authors.lastname: Dobrolecki
authors.affiliation: Department of Pharmacy Practice and Translational Research, University of Houston, Houston, TX, USA. ah.rawi@yahoo.com.
authors.forename: Ahmed
authors.initials: A
authors.lastname: Al-rawi
authors.affiliation: Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX, USA. Fengju.Chen@bcm.edu.
authors.forename: Fengju
authors.initials: F
authors.lastname: Chen
authors.affiliation: Department of Molecular Medicine and Medical Biotechnology, University Federico II, Naples, Italy. venezian@unina.it.
authors.forename: Bianca M
authors.initials: BM
authors.lastname: Veneziani
authors.affiliation: Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX, USA. xiangz@bcm.edu.|Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX, USA. xiangz@bcm.edu.|Department of Medicine, Baylor College of Medicine, Houston, TX, USA. xiangz@bcm.edu.|Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA. xiangz@bcm.edu.
authors.forename: Xiang H-F
authors.initials: XH
authors.lastname: Zhang
authors.affiliation: Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX, USA. sgh@bcm.edu.|Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX, USA. sgh@bcm.edu.|Department of Medicine, Baylor College of Medicine, Houston, TX, USA. sgh@bcm.edu.
authors.forename: Susan G
authors.initials: SG
authors.lastname: Hilsenbeck
authors.affiliation: Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX, USA. alejandr@bcm.edu.|Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX, USA. alejandr@bcm.edu.|Department of Pathology, Baylor College of Medicine, Houston, TX, USA. alejandr@bcm.edu.
authors.forename: Alejandro
authors.initials: A
authors.lastname: Contreras
authors.affiliation: Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX, USA. mgutierr@bcm.edu.|Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX, USA. mgutierr@bcm.edu.|Department of Pathology, Baylor College of Medicine, Houston, TX, USA. mgutierr@bcm.edu.
authors.forename: Carolina
authors.initials: C
authors.lastname: Gutierrez
authors.affiliation: Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX, USA. Rinath_Jeselsohn@DFCI.HARVARD.EDU.|Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA. Rinath_Jeselsohn@DFCI.HARVARD.EDU.
authors.forename: Rinath M
authors.initials: RM
authors.lastname: Jeselsohn
authors.affiliation: Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX, USA. rimawi@bcm.edu.|Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX, USA. rimawi@bcm.edu.|Department of Medicine, Baylor College of Medicine, Houston, TX, USA. rimawi@bcm.edu.
authors.forename: Mothaffar F
authors.initials: MF
authors.lastname: Rimawi
authors.affiliation: Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX, USA. kosborne@bcm.edu.|Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX, USA. kosborne@bcm.edu.|Department of Medicine, Baylor College of Medicine, Houston, TX, USA. kosborne@bcm.edu.
authors.forename: C Kent
authors.initials: CK
authors.lastname: Osborne
authors.affiliation: Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX, USA. mtlewis@bcm.edu.|Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX, USA. mtlewis@bcm.edu.|Department of Radiology, Baylor College of Medicine, Houston, TX, USA. mtlewis@bcm.edu.
authors.forename: Michael T
authors.initials: MT
authors.lastname: Lewis
authors.affiliation: Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX, USA. rschiff@bcm.edu.|Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX, USA. rschiff@bcm.edu.|Department of Medicine, Baylor College of Medicine, Houston, TX, USA. rschiff@bcm.edu.|Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA. rschiff@bcm.edu.
authors.forename: Rachel
authors.initials: R
authors.lastname: Schiff
authors.affiliation: Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX, USA. mtrivedi@UH.EDU.|Department of Pharmacy Practice and Translational Research, University of Houston, Houston, TX, USA. mtrivedi@UH.EDU.|Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX, USA. mtrivedi@UH.EDU.|Department of Medicine, Baylor College of Medicine, Houston, TX, USA. mtrivedi@UH.EDU.|Department of Pharmacological and Pharmaceutical Sciences, University of Houston, Houston, TX, USA. mtrivedi@UH.EDU.
authors.forename: Meghana V
authors.initials: MV
authors.lastname: Trivedi
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000401:mortality / Q000473:pathology*; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D005260:Female; D020869:Gene Expression Profiling; D064593:Heterografts; D006801:Humans; D008175:Lung Neoplasms / Q000556:secondary; D051379:Mice; D009362:Neoplasm Metastasis; D009360:Neoplastic Cells, Circulating / Q000378:metabolism / Q000473:pathology*; D011379:Prognosis; D059467:Transcriptome