Modulating Bone Marrow Hematopoietic Lineage Potential to Prevent Bone Metastasis in Breast Cancer
Abstract
The presence of disseminated tumor cells in breast cancer patient bone marrow aspirates predicts decreased recurrence-free survival. Although it is appreciated that physiologic, pathologic, and therapeutic conditions impact hematopoiesis, it remains unclear whether targeting hematopoiesis presents opportunities for limiting bone metastasis. Using preclinical breast cancer models, we discovered that marrow from mice treated with the bisphosphonate zoledronic acid (ZA) are metastasis-suppressive. Specifically, ZA modulated hematopoietic myeloid/osteoclast progenitor cell (M/OCP) lineage potential to activate metastasis-suppressive activity. Granulocyte-colony stimulating factor (G-CSF) promoted ZA resistance by redirecting M/OCP differentiation. We identified M/OCP and bone marrow transcriptional programs associated with metastasis suppression and ZA resistance. Analysis of patient blood samples taken at randomization revealed that women with high-plasma G-CSF experienced significantly worse outcome with adjuvant ZA than those with lower G-CSF levels. Our findings support discovery of therapeutic strategies to direct M/OCP lineage potential and biomarkers that stratify responses in patients at risk of recurrence.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Sep 14, 2018
- Source ID
- 10.1158/0008-5472.can-18-0548
Entities
People
- Ana C Garrido-Castro
- Catherine S. Rhee
- David T. Scadden
- Ingunn Holen
- Jaclyn Sceneay
- Janet E. Brown
- Jessalyn M. Ubellacker
- John N Hutchinson
- Marie-therese Haider
- Molly J. Decristo
- Nicolas Severe
- Ninib Baryawno
- Robert E. Coleman
- Sandra S McAllister
- Walter Martin Gregory
- Yuanbo Qin
Organizations
- Brigham and Women's Hospital
- Dana–Farber Cancer Institute
- Harvard Medical School
- Harvard University
- Massachusetts General Hospital
- National Cancer Institute
- National Institutes of Health
- United States Department of Defense
- University of Leeds
- University of Sheffield