title: Hematopoietic Age at Onset of Triple-Negative Breast Cancer Dictates Disease Aggressiveness and Progression.
abstract: Triple-negative breast cancer (TNBC) is considered an early onset subtype of breast cancer that carries with it a poorer prognosis in young rather than older women for reasons that remain poorly understood. Hematopoiesis in the bone marrow becomes altered with age and may therefore affect the composition of tumor-infiltrating hematopoietic cells and subsequent tumor progression. In this study, we investigated how age- and tumor-dependent changes to bone marrow-derived hematopoietic cells impact TNBC progression. Using multiple mouse models of TNBC tumorigenesis and metastasis, we found that a specific population of bone marrow cells (BMC) upregulated CSF-1R and secreted the growth factor granulin to support stromal activation and robust tumor growth in young mice. However, the same cell population in old mice expressed low levels of CSF1R and granulin and failed to promote tumor outgrowth, suggesting that age influences the tumorigenic capacity of BMCs in response to tumor-associated signals. Importantly, BMCs from young mice were sufficient to activate a tumor-supportive microenvironment and induce tumor progression in old mice. These results indicate that hematopoietic age is an important determinant of TNBC aggressiveness and provide rationale for investigating age-stratified therapies designed to prevent the protumorigenic effects of activated BMCs. Cancer Res; 76(10); 2932-43. ©2016 AACR.
authors.affiliation: Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts.
authors.forename: Timothy
authors.initials: T
authors.lastname: Marsh
authors.affiliation: Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts.
authors.forename: Irene
authors.initials: I
authors.lastname: Wong
authors.affiliation: Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts. Harvard Medical School, Boston, Massachusetts.
authors.forename: Jaclyn
authors.initials: J
authors.lastname: Sceneay
authors.affiliation: Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts.
authors.forename: Amey
authors.initials: A
authors.lastname: Barakat
authors.affiliation: Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts. Harvard Medical School, Boston, Massachusetts.
authors.forename: Yuanbo
authors.initials: Y
authors.lastname: Qin
authors.affiliation: Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts.
authors.forename: Andreas
authors.initials: A
authors.lastname: Sjödin
authors.affiliation: Department of Cell Biology and Physiology; Department of Medicine; and ICCE Institute, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: Elise
authors.initials: E
authors.lastname: Alspach
authors.affiliation: Division of Hematology and Transfusion Medicine, Department of Laboratory Medicine, Lund University, Lund, Sweden. Broad Institute of Harvard and MIT, Cambridge, Massachusetts.
authors.forename: Björn
authors.initials: B
authors.lastname: Nilsson
authors.affiliation: Department of Cell Biology and Physiology; Department of Medicine; and ICCE Institute, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: Sheila A
authors.initials: SA
authors.lastname: Stewart
authors.affiliation: Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts. Harvard Medical School, Boston, Massachusetts. Broad Institute of Harvard and MIT, Cambridge, Massachusetts. Harvard Stem Cell Institute, Cambridge, Massachusetts. smcallister1@partners.org.
authors.forename: Sandra S
authors.initials: SS
authors.lastname: McAllister
mesh_terms: D000367:Age Factors; D017668:Age of Onset; D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D001854:Bone Marrow Cells / Q000378:metabolism / Q000473:pathology*; D049109:Cell Proliferation; D018450:Disease Progression; D005260:Female; D005434:Flow Cytometry; D006410:Hematopoiesis / Q000502:physiology*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D000077153:Progranulins; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D016187:Receptors, Granulocyte-Macrophage Colony-Stimulating Factor / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D064726:Triple Negative Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D014407:Tumor Cells, Cultured; D059016:Tumor Microenvironment; D023041:Xenograft Model Antitumor Assays
chemical_list: C000604004:Csf1r protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; D000077153:Progranulins; D012333:RNA, Messenger; D016187:Receptors, Granulocyte-Macrophage Colony-Stimulating Factor