Abstract 89: Parathyroid Hormone-related Protein (PTHrP) is critical for breast tumour metastasis and may constitute a novel target for therapeutic intervention.
Authors: Jiarong Li, Andrew C. Karaplis, Dao C. Huang, Peter M. Siegel, Anne Camirand, Xian Fang Yang1, William J. Muller, Richard Kremer
Journal: Cancer Research (2013)

Abstract An increase in PTHrP circulating levels is associated with breast cancer recurrence and reduced survival. Despite the frequent association of PTHrP dysregulation with many tumor types, a precise and direct role for PTHrP in cancer development and progression has been difficult to prove, and its involvement in tumor initiation in vivo and in critical steps of malignant conversion is not clear. In this study, mice carrying a conditional PTHrP allele were crossed with the PyVMT transgenic mouse mammary tumor model and then with a separate transgenic strain expressing Cre in the mammary epithelium (MMTV/Cre). Circulating tumor cells (CTCs) were detectable in animals with PyVMT-PTHrPflox/flox-Cre−phenotype but not in animals with PyVMT-PTHrPflox/flox-Cre+ phenotype. The invasive ability in vitro of PyVMT-PTHrPflox/flox-Cre+cells was reduced by over 80% (P&amp;lt;0.001) as compared to control cells (PyVMT-PTHrP flox/flox-Cre−). Metastatic spread to lungs was seen in 100% of animals with PyVMT-PTHrP flox/flox-Cre− phenotype but none of the animals with PyVMT-PTHrP flox/flox-Cre+ phenotype. AKT1 and CXCR4 expression by Western blot and confocal microscope in both isolated cells and tumors from both genotypes. Akt 1 and CXCR4 expression by Western blot and immunofluorescence were markedly reduced (over 80% P&amp;lt;0.001) in PyVMT-PTHrPflox/flox-Cre+cells and tumors as compared to PyVMT-PTHrPflox/flox-Cre− cells and tumors. Anti-PTHrP neutralizing mAbs significantly inhibited matrigel invasion by human MDA-MB-435 breast cancer and their growth in vivo when injected into the MFPs of BALB/c nu/nu mice. After 6 weeks, approximately 100% of control animals presented lung metastases in contrast with 33% for mAb-treated mice the mAbs antibody reduced the expression of CXCR4 and AKT1 in mammary tumours by over 80% these results suggest that anti-PTHrP antibodies can be considered for therapeutic use against human breast cancer progression. Overall,our study demonstrates that PTHrP plays a crucial role in metastatic spread possibly by altering critical checkpoint of cancer progression and suggest its potential usefulness to prevent progression and recurrence of breast cancer. These results also suggest that anti-PTHrP antibodies can be considered for therapeutic use against human breast cancer progression. Citation Format: Jiarong Li, Andrew C. Karaplis, Dao C. Huang, Peter M. Siegel, Anne Camirand, Xian Fang Yang1, William J. Muller, Richard Kremer. Parathyroid Hormone-related Protein (PTHrP) is critical for breast tumour metastasis and may constitute a novel target for therapeutic intervention. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 89. doi:10.1158/1538-7445.AM2013-89