Abstract 2966: Stromal platelet derived growth factor receptor-beta (PDGFRbeta) promotes breast cancer progression
Authors: Sizemore Gina M. , Hammer Anisha M. , Thies Katie A. , Sizemore Steven T. , Trimboli Anthony J. , Hildreth B. Eason , Kladney Raleigh D. , Chakravarti Arnab , Leone Gustavo , Ostrowski Michael C. 
Published: July 2017

Abstract
Over the past decade it has become evident that the tumor microenvironment (TME) actively participates in carcinogenesis. Tumor-associated fibroblasts, for example, modulate neighboring tumor epithelium through growth factor secretion to initiate and promote tumor growth. The platelet derived growth factor receptors (PDGFRs), PDGFRalpha and PDGFRbeta, are receptor tyrosine kinases activated by PDGF that may be critical and actionable mediators of breast tumor-stromal communication. PDGFRs are predominately expressed in breast tumor stroma while their cognate ligands are specifically expressed in tumor epithelium and associated endothelium. In some cancers, tumor-derived PDGFs act on the TME to recruit tumor associated fibroblasts; however, this role has not been described in breast cancer. To begin to evaluate a role for PDGFRbeta, we utilized publicly available gene expression data to confirm upregulation in tumor stroma compared to tumor epithelium. Importantly, PDGFRB is increased in tumor stroma compared to normal stroma. To directly test whether stromal PDGFR activation promotes tumor growth, we co-injected murine mammary tumor cells with or without PDGFR-expressing mouse mammary fibroblasts (MMFs) orthotopically in FVB/N mice. MMF inclusion increased tumor cell proliferation as well as associated angiogenesis while systemic treatment with imatinib mesylate, a small molecule inhibitor for PDGFR, restored both proliferation and angiogenesis back to baseline. These findings indicated the importance of PDGFR signaling in tumor initiation leading us to develop a mouse model of stromal-specific PDGFRbeta activation using the Fsp-cre transgene previously published by our group (henceforth referred to as “PDGFRbeta mutant”). PDGFRbeta mutant mammary glands exhibit increased tertiary side-branching and epithelial proliferation confirming a stromal-specific PDGFRbeta effect on neighboring epithelium during development. Further, MMFs isolated from the PDGFRbeta mutant mice exhibit increased motility towards PDGF-B expressing tumor cells in vitro, which implies increased response and recruitment of the mutant MMFs towards an expanding tumor. To test whether PDGFRbeta mutant mice harbor a mammary TME supportive of increased tumor growth, we injected murine mammary tumor cells orthotopically into either control or PDGFRbeta mutant mice finding that the time required to meet early removal criteria (tumor &gt1.2cm3) was shorter in the mutant mice compared to controls. Ongoing studies are evaluating whether systemic PDGFR inhibition will abrogate this observed increase in tumorigenesis. In summary, our data suggest that stromal PDGFRbeta signaling is pro-tumorigenic in breast cancer and that inhibition using well-described PDGFR inhibitors could be a valid therapeutic approach for women whose tumors express increased PDGF-to-PDGFR tumor-stromal signaling.
Citation Format: Gina M. Sizemore, Anisha M. Hammer, Katie A. Thies, Steven T. Sizemore, Anthony J. Trimboli, B. Eason Hildreth, Raleigh D. Kladney, Arnab Chakravarti, Gustavo Leone, Michael C. Ostrowski. Stromal platelet derived growth factor receptor-beta (PDGFRbeta) promotes breast cancer progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2966. doi:10.1158/1538-7445.AM2017-2966