PTHrP drives breast tumor initiation, progression, and metastasis in mice and is a potential therapy target
Jiarong Li, Andrew C. Karaplis, Dao C. Huang, Peter M. Siegel, Anne Camirand, Xian Fang Yang, William J. Muller, Richard Kremer
Jiarong Li, Andrew C. Karaplis, Dao C. Huang, Peter M. Siegel, Anne Camirand, Xian Fang Yang, William J. Muller, Richard Kremer
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Research Article Oncology

PTHrP drives breast tumor initiation, progression, and metastasis in mice and is a potential therapy target

Abstract

Parathyroid hormone–related protein (PTHrP) is a secreted factor expressed in almost all normal fetal and adult tissues. It is involved in a wide range of developmental and physiological processes, including serum calcium regulation. PTHrP is also associated with the progression of skeletal metastases, and its dysregulated expression in advanced cancers causes malignancy-associated hypercalcemia. Although PTHrP is frequently expressed by breast tumors and other solid cancers, its effects on tumor progression are unclear. Here, we demonstrate in mice pleiotropic involvement of PTHrP in key steps of breast cancer — it influences the initiation and progression of primary tumors and metastases. Pthrp ablation in the mammary epithelium of the PyMT-MMTV breast cancer mouse model caused a delay in primary tumor initiation, inhibited tumor progression, and reduced metastasis to distal sites. Mechanistically, it reduced expression of molecular markers of cell proliferation (Ki67) and angiogenesis (factor VIII), antiapoptotic factor Bcl-2, cell-cycle progression regulator cyclin D1, and survival factor AKT1. PTHrP also influenced expression of the adhesion factor CXCR4, and coexpression of PTHrP and CXCR4 was crucial for metastatic spread. Importantly, PTHrP-specific neutralizing antibodies slowed the progression and metastasis of human breast cancer xenografts. Our data identify what we believe to be new functions for PTHrP in several key steps of breast cancer and suggest that PTHrP may constitute a novel target for therapeutic intervention.

Authors

Jiarong Li, Andrew C. Karaplis, Dao C. Huang, Peter M. Siegel, Anne Camirand, Xian Fang Yang, William J. Muller, Richard Kremer

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Figure 10

Anti-PTHrP neutralizing mAbs inhibit breast cancer progression in vitro and in vivo.

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Anti-PTHrP neutralizing mAbs inhibit breast cancer progression in vitro ...
(A) Proliferation in Matrigel (24 hours) of human MDA-MB-435 breast cancer cells showing growth-inhibition effect of neutralizing antibodies 158 and M45 in vitro.*P < 0.05. (B) Tumor volume over time after injection of MDA-MB-435 cells into the MFPs of BALB/c nu/nu mice and treatment with anti-PTHrP mAbs, showing the tumor-reducing effect in vivo. Data are expressed as means of 8 mice in each group. *P < 0.05; **P < 0.01. (C) IF confocal images of mammary tumors 6 weeks after injection of MDA-MB-435 cells in MFPs of nude mice showing decrease of CXCR4 (top panels) and AKT1 (bottom panels) in treated animals. Shown are DAPI (blue), CXCR4 (green), and AKT1 (red). (D) H&E staining of lung metastases 6 weeks after injection of MDA-MB-435 in MFPs. Treatment with anti-PTHrP mAbs reduces the size and numbers of lung metastases. (E–G) Fewer mice present lung metastases after treatment with either mAb, and the metastases are smaller and fewer in numbers in treated animals. Mean ± SEM. *P < 0.05 (E); *P = 0.013 (F); *P = 0.045 (G). (H) IF confocal images of lung metastases in nude mice injected with MDA-MB-435 cells treated (6 weeks) or not with anti-PTHrP mAbs. Lung metastases are CXCR4 positive irrespective of treatment. Shown are DAPI (blue) and CXCR4 (green). Scale bars: 100 μm (A); 50 μm (C and H); 200 μm (D).