PTHrP drives breast tumor initiation, progression, and metastasis in mice and is a potential therapy target
Jiarong Li, … , William J. Muller, Richard Kremer
Jiarong Li, … , William J. Muller, Richard Kremer
Published November 7, 2011
Citation Information: J Clin Invest. 2011;121(12):4655-4669. https://doi.org/10.1172/JCI46134.
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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 8

PTHrP drives metastatic spread.

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PTHrP drives metastatic spread. (A) Matrigel growth of tumor cells from ...
(A) Matrigel growth of tumor cells from Pthrpflox/flox;Cre– or Pthrpflox/flox;Cre+ tumors and histogram showing reduced invasive capacity for ablated cells (22 hours). **P < 0.01. (B) Cell motility test after wounding (48 hours); Pthrp-ablated cells show slower motility than control cells. (C) Epimet stain of cytospins for detection of circulating tumor cells (arrowheads show pan-cytokeratin–positive cells, 18 weeks). No tumor cells are detectable in blood of homozygous mice. (D) Tumor cells flushed from bone marrow (IF stain: cytokeratin 8/PyMT double positives) in control animals only. (E) Lung metastases are slower to appear in heterozygous mice. (F and G) Lung metastases appear in homozygous mice even later (between 13 and 18 weeks). (H and I) Lung metastases after MFP injection of adenovirus-transfected tumor cells. Lung metastases appear earlier in control mice than in the spontaneous tumor model (E and G), but are not detectable in homozygous ablated mice (adenovirus transfected) at 16 weeks. (All groups for E to I, n = 9). Scale bars: 100 μm (A–C); 50 μm (D); 200 μm (E, F, and H). Error bars represent SD. Large single and double asterisks refer to corresponding stages in Figure 9.