Parathyroid hormone 1 receptor signaling mediates breast cancer metastasis to bone in mice

Sep 24, 2026

Bone metastases are a frequent and debilitating complication of advanced breast cancer. Intermittent administration of parathyroid hormone (PTH[1-34]) previously showed reduced bone metastasis in murine models via effects on osteoblasts. This study tests how PTH1R-mediated signaling in osteoblasts and breast cancer cells controls metastatic progression, focusing on migration and the role of PTH-related protein (PTHrP) in a vicious bone-resorption cycle.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages16

Reading Time40 min

AccessFree to download

Introduction

Background: bone metastasis and skeletal complications

RANKL/OPG vicious cycle driven by PTHrP

Antiresorptive therapy limitations

Osteoporosis analog therapies and anabolic agents

Rationale for intermittent PTH and PTH1R signaling

RESE AR CH ARTICLE Conflict of interest: The authors have declared that no conflict of interest exists. Copyright: © 2023, Swami et al. This is an open access article published under the terms of the Creative Commons Attribution 4.0 International License. Submitted: December 17, 2021 Accepted: January 23, 2023 Published: March 8, 2023 Reference information: JCI Insight. 2023;8(5):e157390 . [https://doi.org/10.1172/jci](https://doi.org/10.1172/jci). insight.157390 . Parathyroid hormone 1 receptor signaling mediates breast cancer metastasis to bone in mice Srilatha Swami, Hui Zhu, Aria Nisco, Takaharu Kimura, Matthew J. Kim, Vaisakh Nair, and Joy Y. Wu Department of Medicine, Division of Endocrinology, Stanford University School of Medicine, Stanford, California, USA. Bone metastases are a common complication of breast cancer. We have demonstrated that intermittent administration of parathyroid hormone (PTH[1-34]) reduces the incidence of bone metastases in murine models of breast cancer by acting on osteoblasts to alter the bone microenvironment. Here, we examined the role of signaling mediated by PTH 1 receptor (PTH1R) in both osteoblasts and breast cancer cells in influencing bone metastases. In mice with impaired PTH1R signaling in osteoblasts, intermittent PTH did not reduce bone metastasis. Intermittent PTH also did not reduce bone metastasis when expression of PTH1R was knocked down in 4T1 murine breast cancer cells by shRNA. In 4T1 breast cancer cells, PTH decreased expression of PTH-related protein (PTHrP), implicated in the vicious cycle of bone metastases. Knockdown of PTHrP in 4T1 cells significantly reduced migration toward MC3T3-E1 osteoblasts, and migration was further inhibited by treatment with intermittent PTH. Conversely, overexpression of PTHrP in 4T1 cells increased migration toward MC3T3-E1 osteoblasts, and this was not inhibited by PTH. In conclusion, PTH1R expression is crucial in both osteoblasts and breast cancer cells for PTH to reduce bone metastases, and in breast cancer cells, this may be mediated in part by suppression of PTHrP. Introduction Breast cancer is the most frequently diagnosed cancer in women and continues to be a leading cause of death in the United States and worldwide (1) . Advanced breast cancer with distant organ metastasis is incurable, and bone is the most common site of metastasis (2, 3) . Bone metastases are characterized by osteolytic lesions and can cause bone loss, pain, fracture, hypercalcemia, and other skeletal adverse events (4) . Although breast cancer therapies are effective and focus mostly on the tumor cells, there is a need for agents that target the skeletal-related events and restore bone integrity. Bone metastasis depends on the ability of the cancer cells to home to and engraft in the bone. Parathyroid hormone–related protein (PTHrP; encoded by Pthlh) is produced by breast cancer cells and increases RANKL (encoded by Tnfsf11) in the bone while reducing osteoprotegrin (OPG; encoded by Tnfrsf11b), thereby shifting the RANKL to OPG ratio to establish a vicious cycle in favor of increased bone resorption (5) . The vicious cycle is further perpetuated by the release into the bone milieu of growth factors present in the bone matrix, such as TGF-β, IGFs, BMPs, and MMPs (5) . These factors promote homing, invasion, colonization, survival, and proliferation of breast cancer cells within bone, leading to increased bone resorption and bone loss. Antiresorptive drugs such as bisphosphonates and denosumab (an mAb targeted against the osteoclast differentiation factor RANKL) are highly effective in reducing the adverse skeletal events related to bone metastases (6) . However, antiresorptive medications do not support the new bone formation needed to restore skeletal integrity, and high cumulative doses are associated with osteonecrosis of the jaw and atypical fractures (7, 8) . Hence, strategies that preserve bone health and restore bone loss

FAQs

What is the main aim of this study?

To determine how PTH1R-mediated signaling in osteoblasts and breast cancer cells regulates bone metastasis in mice, and to evaluate whether PTH effects involve changes in PTHrP-dependent pathways.

Does intermittent PTH reduce bone metastasis when PTH1R signaling is impaired in osteoblasts?

No. In mice with impaired PTH1R signaling in osteoblasts, intermittent PTH did not reduce bone metastasis.

How does PTH affect PTHrP in breast cancer cells and cell migration?

In 4T1 breast cancer cells, PTH decreased PTHrP expression and reduced migration toward osteoblasts. Conversely, PTHrP overexpression increased migration and was not inhibited by PTH.

Sep 24, 2026

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