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Prevention of breast cancer skeletal metastases with parathyroid hormone
Srilatha Swami, … , Rachelle W. Johnson, Joy Y. Wu
Srilatha Swami, … , Rachelle W. Johnson, Joy Y. Wu
Published September 7, 2017
Citation Information: JCI Insight. 2017;2(17):e90874. https://doi.org/10.1172/jci.insight.90874.
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Research Article Bone biology Oncology

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.

Authors

Srilatha Swami, Joshua Johnson, Lance A. Bettinson, Takaharu Kimura, Hui Zhu, Megan A. Albertelli, Rachelle W. Johnson, Joy Y. Wu

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Figure 7

In vitro treatment with intermittent PTH attenuates the migratory potential of breast cancer cells by altering the gene expression profile in preosteoblastic MC3T3-E1 cells.

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In vitro treatment with intermittent PTH attenuates the migratory potent...
Numbers of breast cancer cells (4T1 and MDA) that migrated towards MC3T3-E1 preosteoblastic cells treated with (A) continuous PTH, (B) intermittent PTH, or (C) conditioned media from cells treated with intermittent PTH in a Transwell migration system. (D) Target gene expression in MC3T3-E1 cells using gene-specific primers. (E) RT2 Profiler Tumor PCR Metastasis PCR Array analysis of MC3T3-E1 gene expression. (F) Genes with >2 fold changes from Table 3 were further validated with real-time quantitative PCR. (G) CXCL12 protein levels in MC3T3-E1 cells treated with control or PTH in the absence or presence of 4T1 cells. All values represent mean ± SEM of at least 3 individual experiments conducted in triplicate. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001 when compared with control (con) group. +++P < 0.001 when compared with control (+4T1), by 1-way ANOVA with Bonferroni’s test as post-hoc analysis.

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