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      Prevention of breast cancer skeletal metastases with parathyroid hormone

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          Abstract

          Advanced breast cancer is frequently associated with skeletal metastases and accelerated bone loss. Recombinant parathyroid hormone [teriparatide, PTH(1-34)] is the first anabolic agent approved in the US for treatment of osteoporosis. While signaling through the PTH receptor in the osteoblast lineage regulates bone marrow hematopoietic niches, the effects of anabolic PTH on the skeletal metastatic niche are unknown. Here, we demonstrate, using orthotopic and intratibial models of 4T1 murine and MDA-MB-231 human breast cancer tumors, that anabolic PTH decreases both tumor engraftment and the incidence of spontaneous skeletal metastasis in mice. Microcomputed tomography and histomorphometric analyses revealed that PTH increases bone volume and reduces tumor engraftment and volume. Transwell migration assays with murine and human breast cancer cells revealed that PTH alters the gene expression profile of the metastatic niche, in particular VCAM-1, to inhibit recruitment of cancer cells. While PTH did not affect growth or migration of the primary tumor, it elicited several changes in the tumor gene expression profile resulting in a less metastatic phenotype. In conclusion, PTH treatment in mice alters the bone microenvironment, resulting in decreased cancer cell engraftment, reduced incidence of metastases, preservation of bone microarchitecture and prolonged survival.

          Abstract

          Effects of anabolic PTH on the bone microenvironment negatively impacts breast cancer migration, leading to reduced cancer cell engraftment and incidence of skeletal metastasis in mice models.

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          Author and article information

          Contributors
          Journal
          JCI Insight
          JCI Insight
          JCI Insight
          JCI Insight
          American Society for Clinical Investigation
          2379-3708
          7 September 2017
          7 September 2017
          7 September 2017
          : 2
          : 17
          : e90874
          Affiliations
          [1 ]Department of Medicine, Division of Endocrinology, Stanford University School of Medicine, Stanford, California, USA.
          [2 ]Department of Medicine, Division of Clinical Pharmacology, and
          [3 ]Vanderbilt Center for Bone Biology, Vanderbilt University Medical Center, Vanderbilt University, Nashville, Tennessee, USA.
          [4 ]Department of Comparative Medicine and
          [5 ]Department of Radiation Oncology, Division of Radiation and Cancer Biology, Stanford University School of Medicine, Stanford, California, USA.
          [6 ]Department of Cancer Biology, Vanderbilt University, Nashville, Tennessee, USA.
          Author notes
          Address correspondence to: Joy Y. Wu, Stanford University School of Medicine, 300 Pasteur Drive, Room S025, Stanford California 94305-5103, USA. Phone: 650.736.9654; Email: jywu1@ 123456stanford.edu .
          Article
          PMC5621896 PMC5621896 5621896 90874
          10.1172/jci.insight.90874
          5621896
          28878134
          35b4f8c5-baf0-4a32-9664-9dc4d43a7ad7
          Copyright © 2017, American Society for Clinical Investigation
          History
          : 26 September 2016
          : 27 July 2017
          Funding
          Funded by: The Mary Kay Foundation
          Award ID: Cancer Research Grant
          Funded by: NIH
          Award ID: DP2OD008466
          Funded by: NIH
          Award ID: K99CA194198
          to JYW
          to JYW
          to RWJ
          Categories
          Research Article

          Breast cancer,Bone Biology,Oncology,Bone disease,G-protein coupled receptors

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