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Dysregulated protease activated receptor 1 (PAR1) promotes metastatic phenotype in breast cancer through HMGA2

Oncogene volume 35, pages 1529–1540 (2016)Cite this article

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Abstract

As the majority of patients with basal-like breast carcinoma present with invasive, metastatic disease that do not respond to available therapies, it is essential to identify new therapeutic targets that impact invasion and metastasis. Protease-activated receptor 1 (PAR1), a G-protein coupled receptor has been shown to act as an oncogene, but underlying mechanisms are not well understood. Here, we show that ectopic expression of functionally active PAR1 in MCF-7 cells induced a hormone-refractory, invasive phenotype representative of advanced basal-like breast carcinoma that readily formed metastatic lesions in lungs of mice. PAR1 was found to globally upregulate mesenchymal markers, including vimentin, a direct target of PAR1, and downregulate the epithelial markers including E-cadherin, as well as estrogen receptor. In contrast, non-signaling PAR1 mutant receptor did not lead to an invasive, hormone refractory phenotype. PAR1 expression increased spheroid formation and the level of stemness markers and self-renewal capacity in human breast cancer cells. We identified HMGA2 (high mobility group A2) as an important regulator of PAR1-mediated invasion. Inhibition of PAR1 signaling suppresses HMGA2-driven invasion in breast cancer cells. HMGA2 gene and protein are highly expressed in metastatic breast cancer cells. Overall, our results show that PAR1/HMGA2 pathway may present a novel therapeutic target.

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Acknowledgements

We thank Vishal Trivedi, Chris Parkin, Akiko Hata, Larry Feig and Anna Wronski for their expert advice and Ryan Stevenson for critically reading the manuscript. The microarray analysis was carried out in the Genomics Core of the Tufts Center for Neuroscience Research, Tufts University School of Medicine (supported by NNDS – P30 NS047243). This work was supported by NIH grants CA104406 (LC), Susan G. Komen BCTR0706763, Diane Connolly-Zaniboni Research Scholarship (LC) and a fellowship from Aid for Cancer Research, Boston, MA (EY) by NIH CA122992, HL64701 (to AK).

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Authors and Affiliations

  1. Molecular Oncology Research Institute,

    E Yang, J Cisowski, N Nguyen, K O'Callaghan, J Xu, A Agarwal, A Kuliopulos & L Covic

  2. , Tufts Medical Center, Boston, MA, USA

    E Yang, J Cisowski, N Nguyen, K O'Callaghan, J Xu, A Agarwal, A Kuliopulos & L Covic

  3. Department of Biochemistry and Tufts Medical Center, Boston, MA, USA

    E Yang, A Kuliopulos & L Covic

  4. Division of Hematology/Oncology, Tufts Medical Center, Boston, MA, USA

    A Kuliopulos & L Covic

  5. Department of Medicine, Tufts Medical Center, Boston, MA, USA

    A Kuliopulos & L Covic

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  1. E Yang
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  2. J Cisowski
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  3. N Nguyen
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  4. K O'Callaghan
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  6. A Agarwal
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  8. L Covic
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Correspondence to L Covic.

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Yang, E., Cisowski, J., Nguyen, N. et al. Dysregulated protease activated receptor 1 (PAR1) promotes metastatic phenotype in breast cancer through HMGA2. Oncogene 35, 1529–1540 (2016). https://doi.org/10.1038/onc.2015.217

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