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

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 3

Intermittent PTH reduces skeletal metastases in a treatment model of 4T1 murine breast cancer.

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Intermittent PTH reduces skeletal metastases in a treatment model of 4T1...
(A) Treatment model experimental design. Mice were 10 weeks old at the time of 4T1 cell injection (B) Representative BLI images of metastases to the hind limbs in the treatment model. (C) Quantitation of BLI in lungs, liver, spleen, and hind limbs with metastases in the treatment model. (D) Representative sections of double calcein labeling in hind limbs with metastases from mice treated with PBS/PTH. Sections are stained with xylene orange to visualize calcein labeling (indicated with white arrowheads) or H&E to visualize corresponding histology (areas of tumor are indicated with dotted lines). Scale bar: 200 μm. (E) BLI at week 3 following PBS and PTH treatment in tumor-bearing mice (n = 5) in mice prior to flow cytometry. (F) Flow cytometry for detection of GFP+ 4T1 cells in bones of PBS- and PTH-treated mice (n = 5). In mice treated with PBS, GFP+ 4T1 cells were detected in the hind limb bones of 1 of 5 animals at weeks 1 and 2 and in 5 of 5 mice at week 3. In PTH-treated mice, GFP+ 4T1 cells were detected in 0 of 5 mice at weeks 1 and 2 and in 2 of 5 mice at week 3. Hind limbs injected intratibially with 4T1 cells were used as positive (+) controls. (G) Flow cytometry for detection of GFP+ 4T1 cells in bone marrow (n = 5). No GFP+ 4T1 cells were detected by flow cytometry in bone marrow from any of the 5 PBS- or PTH-treated mice at weeks 1, 2, or 3. All values represent mean ± SD. *P < 0.05 when compared with PBS-treated group, by 1-way ANOVA with Bonferroni’s test as post-hoc analysis.