Abstract P6-06-06: Platelet derived growth factor-b (PDGFB) promotes breast cancer progression

Objectives of the Study: Platelet-derived growth factor (PDGF) mediated signaling is pro-tumorigenic in many types of cancer, including breast cancer. However, the requirement of individual PDGF ligands in mediating breast cancer progression remains unclear. Our evaluation of publicly available breast cancer patient datasets shows that high primary tumor expression of PDGFB correlates with reduced overall survival (OS) and reduced metastasis free survival (MFS). This is in contrast to the lack of prognostic power of PDGFA and PDGFC and the association with improved OS and MFS for PDGFD. Based on our analysis of patient datasets, we set out to test the requirement of PDGFB in mammary tumor growth. Methods Used: Gain-of-function and loss-of-function experiments were performed wherein PDGFB was either overexpressed or knocked-down in mammary tumor cells. Manipulated tumor cells were injected directly into the mammary fat pads of adult female mice, and tumor growth was monitored over time. PDGFB is produced by tumor cells whereas the corresponding receptor, PDGFRβ, is expressed by mesenchymal cells in the stroma. As another way to mimic oncogenic PDGFB-to-PDGFRβ signaling in the breast, we developed a mouse model of stroma-specific PDGFRβ activation using the Fsp-cre transgene. We evaluated changes mammary gland development upon mesenchymal specific PDGFRβ activation, and performed orthotopic injections with mammary tumor cells in these animals to test the functional role of receptor activation in mammary tumor growth. Results and Conclusions: We evaluated expression of PDGF ligands in FVB/N murine mammary tumor cell lines and found that the PDGFB is dramatically higher in DB7 tumor cells compared to other syngeneic cell lines. In the high-PDGFB expressing DB7 cells, we used shRNA technology to knockdown the ligand. At the same time, we overexpressed the ligand in an isogenic cell line that expresses low levels of PDGFB. These cells were injected orthotopically into the mammary fat pads of adult female mice, and in both cases, expression of PDGFB dictated tumor growth. There was a significant reduction in tumor growth with shRNA-mediated knockdown of PDGFB whereas overexpression of the ligand accelerated tumor growth. In our mouse model of mesenchymal-specific PDGFRβ activation, we reveal that activation of the receptor exerts pro-proliferative signals on adjacent mammary epithelial cells and accelerates orthotopic tumor growth of PDGFB-expressing cells. These findings indicate that PDGFB-to-PDGFRβ signaling is a viable therapeutic target for breast cancer. In fact, treatment with the PDGFR inhibitor, imatinib, impedes tumor cell proliferation when mouse mammary fibroblasts are co-injected orthotopically with DB7 cells. Significance: The requirement of other PDGF ligands in breast cancer remains to be evaluated, but our data support a pro-tumorigenic role for PDGFB in the breast. Importantly, PDGFR inhibitors are being used in clinical trials for several cancer types. Our data advocate for (1) the potential utility of PDGFB as a prognostic biomarker and (2) the pre-clinical evaluation of PDGFR inhibitors in breast cancer models. Citation Format: Katie A Thies, Anisha M Hammer, Sarah A Steck, Manjusri Das, Raleigh D Kladney, Steven T Sizemore, Michael C Ostrowski, Gina M Sizemore. Platelet derived growth factor-b (PDGFB) promotes breast cancer progression [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P6-06-06.