An oncogenic activity of PDGF-C and its splice variant in human breast cancer

Abstract

Despite strong evidence for the involvement of PDGF signaling in breast cancer, little is known about the PDGF ligand responsible for PDGFR activation during breast cancer progression. Here, we found PDGF-C to be highly expressed in breast carcinoma cell lines. Immunohistochemical analysis of invasive breast cancer revealed an association between increased PDGF-C expression and lymph node metastases, Ki-67 proliferation index, and poor disease-free survival. We also identified a PDGF-C splice variant encoding truncated PDGF-C (t-PDGF-C) isoform lacking the signal peptide and the N-terminal CUB domain. While t-PDGF C homodimer is retained intracellularly, it can be secreted as a heterodimer with full-length PDGF-C (FL-PDGF-C). PDGF-C downregulation reduced anchorage-independent growth and matrigel invasion of MDA-MB-231 cells. Conversely, ectopic expression of t-PDGF-C enhanced phenotypic transformation and invasion in BT-549 cells expressing endogenous FL-PDGF-C. The present study provides new insights into the functional significance of PDGF-C and its splice variant in human breast cancer.

Keywords:

• Breast cancer
• growth factors: structure and function
• prognostic marker
• oncogenic activity
• tumor cell invasion

Acknowledgements

We thank Dr. M. Katie Conley-LaComb with her assistance in the preparation of this manuscript, Ms. Lisa Movilla for her assistance with animal experiments, and the Translational Research Core Facility of the Karmanos Cancer Institute for their assistance with analysis of soft agar colony assay. We also thank Dr. Stephen Ethier for providing RNA samples of SUM102, SUM149, and SUM190 cells.

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

This work was supported by NIH/National Cancer Institute RO1 Grants CA064139 and CA123362 (to H-R.C.K.), as well as the Ruth L. Kirschstein National Research Service Awards F32 CA142038 (to A.J.N) and T32-CA009531 (to N.H), and the DoD Breast Cancer Research Program W81XWH-11-1-0029 (to A.B.).