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: Timothy Marsh, Irene Wong, Jaclyn Sceneay, Amey Barakat, Yuanbo Qin, Andreas Sjödin, Elise Alspach, Björn Nilsson, Sheila A Stewart, Sandra S McAllister
• Journal: Cancer research (Cancer Res) Vol. 76 Issue 10 Pg. 2932-43 (05 15 2016) ISSN: 1538-7445 [Electronic] United States
• PMID: 27197230 (Publication Type: Journal Article)
• Copyright: ©2016 American Association for Cancer Research.

Chemical References

• Csf1r protein, mouse
• Intercellular Signaling Peptides and Proteins
• Progranulins
• RNA, Messenger
• Receptors, Granulocyte-Macrophage Colony-Stimulating Factor

Topics

• Age Factors
• Age of Onset
• Animals
• Apoptosis
• Blotting, Western
• Bone Marrow Cells (metabolism, pathology)
• Cell Proliferation
• Disease Progression
• Female
• Flow Cytometry
• Hematopoiesis (physiology)
• Humans
• Intercellular Signaling Peptides and Proteins (genetics, metabolism)
• Mice
• Mice, Nude
• Progranulins
• RNA, Messenger (genetics)
• Real-Time Polymerase Chain Reaction
• Receptors, Granulocyte-Macrophage Colony-Stimulating Factor (genetics, metabolism)
• Reverse Transcriptase Polymerase Chain Reaction
• Triple Negative Breast Neoplasms (genetics, metabolism, pathology)
• Tumor Cells, Cultured
• Tumor Microenvironment
• Xenograft Model Antitumor Assays