title: Differentiation and loss of malignant character of spontaneous pulmonary metastases in patient-derived breast cancer models.
abstract: Patient-derived human-in-mouse xenograft models of breast cancer (PDX models) that exhibit spontaneous lung metastases offer a potentially powerful model of cancer metastasis. In this study, we evaluated the malignant character of lung micrometastases that emerge in such models after orthotopic implantation of human breast tumor cells into the mouse mammary fat pad. Interestingly, relative to the parental primary breast tumors, the lung metastasis (met)-derived mammary tumors exhibited a slower growth rate and a reduced metastatic potential with a more differentiated epithelial status. Epigenetic correlates were determined by gene array analyses. Lung met-derived tumors displayed differential expression of negative regulators of cell proliferation and metabolism and positive regulators of mammary epithelial differentiation. Clinically, this signature correlated with breast tumor subtypes. We identified hsa-miR-138 (miR-138) as a novel regulator of invasion and epithelial-mesenchymal transition in breast cancer cells, acting by directly targeting the polycomb epigenetic regulator EZH2. Mechanistic investigations showed that GATA3 transcriptionally controlled miR-138 levels in lung metastases. Notably, the miR-138 activity signature served as a novel independent prognostic marker for patient survival beyond traditional pathologic variables, intrinsic subtypes, or a proliferation gene signature. Our results highlight the loss of malignant character in some lung micrometastatic lesions and the epigenetic regulation of this phenotype.
authors.affiliation: The Ben May Department for Cancer Research, The University of Chicago, Chicago, Illinois. Stanford Cancer Institute, Stanford University, Stanford, California.
authors.forename: Jessica
authors.initials: J
authors.lastname: Bockhorn
authors.affiliation: Translational Genomics Group, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain. Department of Medical Oncology, Hospital Clínic, Universitat de Barcelona, Barcelona, Spain.
authors.forename: Aleix
authors.initials: A
authors.lastname: Prat
authors.affiliation: The Ben May Department for Cancer Research, The University of Chicago, Chicago, Illinois.
authors.forename: Ya-Fang
authors.initials: YF
authors.lastname: Chang
authors.affiliation: Deparment of Pathology, Case Comprehensive Cancer Center, and National Center for Regenerative Medicine, Case Western Reserve University, Cleveland, Ohio.
authors.forename: Xia
authors.initials: X
authors.lastname: Liu
authors.affiliation: Deparment of Pathology, Case Comprehensive Cancer Center, and National Center for Regenerative Medicine, Case Western Reserve University, Cleveland, Ohio.
authors.forename: Simo
authors.initials: S
authors.lastname: Huang
authors.affiliation: Illinois Institute of Technology, Chicago, Illinois.
authors.forename: Meng
authors.initials: M
authors.lastname: Shang
authors.affiliation: Center for Clinical Cancer Genetics, Department of Medicine, The University of Chicago, Chicago, Illinois.
authors.forename: Chika
authors.initials: C
authors.lastname: Nwachukwu
authors.affiliation: Center for Clinical Cancer Genetics, Department of Medicine, The University of Chicago, Chicago, Illinois.
authors.forename: Maria J
authors.initials: MJ
authors.lastname: Gomez-Vega
authors.affiliation: Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
authors.forename: J Chuck
authors.initials: JC
authors.lastname: Harrell
authors.affiliation: Center for Clinical Cancer Genetics, Department of Medicine, The University of Chicago, Chicago, Illinois.
authors.forename: Olufunmilayo I
authors.initials: OI
authors.lastname: Olopade
authors.affiliation: Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
authors.forename: Charles M
authors.initials: CM
authors.lastname: Perou
authors.affiliation: Deparment of Pathology, Case Comprehensive Cancer Center, and National Center for Regenerative Medicine, Case Western Reserve University, Cleveland, Ohio. hliu@case.edu.
authors.forename: Huiping
authors.initials: H
authors.lastname: Liu
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D000071221:Enhancer of Zeste Homolog 2 Protein; D044127:Epigenesis, Genetic; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000473:pathology / Q000556:secondary; D051379:Mice; D035683:MicroRNAs / Q000235:genetics; D063151:Polycomb Repressive Complex 2 / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
chemical_list: C546110:MIRN138 microRNA, human; D035683:MicroRNAs; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D063151:Polycomb Repressive Complex 2