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 6

PTHrP is involved in CXCR4 and AKT expression control.

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PTHrP is involved in CXCR4 and AKT expression control. (A) Western blot ...
(A) Western blot showing decreased CXCR4 expression in homozygous tumors. (B) Confocal images of IF. Top: primary breast tumors (control 13 weeks, homozygous mice 18 weeks). Bottom: cells isolated from these tumors and cultured. CXCR4 expression is significantly reduced with Pthrp ablation. Residual cells that escaped Pthrp ablation and are still expressing PTHrP are the only ones expressing CXCR4 (arrowheads). (C) IHC (left) and IF (right) images for AKT1 and AKT2 in tumors from control and ablated mice. Shown are DAPI (blue), AKT1 (top, red), and AKT2 (bottom, red). (D) Western blot showing decrease in AKT1 and increase in AKT2 concurrent with Pthrp ablation. (E) Confocal images of IF staining of cultured cells from control (top) and homozygous (bottom) tumors. The residual cells that escaped ablation and are still expressing PTHrP also express AKT1, although a small level of AKT1 is detectable in PTHrP-negative cells. Shown are DAPI (blue), PTHrP (green), and AKT1 (red). (F) Western blot of tumor extracts for AKT1 Ser473 phosphorylation. Scale bars: 50 μm.