Abstract 4083: Deletion of the BMP receptor BMPR1a results in EMT and impairs mammary gland tumor formation and metastasis

Abstract

Abstract Bone Morphogenetic Proteins (BMPs) are secreted cytokines/growth factors belonging to the Transforming Growth Factor β (TGFβ) superfamily. BMP ligands have recently been shown to be overexpressed in human breast cancers. Normal and cancerous breast display active BMP signaling as indicated by phosphorylated Smads 1, 5 and 9. We combined mice expressing the MMTV.PyVmT oncogene with mice lacking BMPR1a in mammary epithelial cells and found this deletion resulted in delayed tumor onset and extended survival significantly (p-value = <0.001). We examined the histopathology of BMPR1a knockout (cKO) tumors and found a striking loss of epithelial characteristics combined with stromal desmoplasia. Immunofluorescence staining revealed that cKO tumors co-expressed Keratin 5 and mesenchymal cell markers such as Vimentin. This indicated that epithelial-to-mesenchymal (EMT)-like transitions were occurring in cKO tumors. We performed microarray analysis on these tumors and found changes that supported EMT-like changes with increased Snail mRNA expression. We established primary tumor cell lines and found that BMPR1a cKO had slower growth in vitro and upon in vivo implantation. Additionally, cKO tumor cells had reduced migration yet not invasion in vitro. We next analyzed human databases from TCGA and survival data from microarrays to confirm BMPR1a tumor promoting functions and found high BMPR1a gene expression correlated with worse survival regardless of molecular breast cancer subtype. In conclusion, we found that loss of the BMPR1a impairs tumor formation and progression and does not exhibit tumor suppressive functions in mouse and human breast cancer. Citation Format: Laura D. Hover, Michael W. Pickup, Agnieszka E. Gorska, Anna Chytil, Yan Guo, Sergey V. Novitskiy, Harold L. Moses, Philip Owens. Deletion of the BMP receptor BMPR1a results in EMT and impairs mammary gland tumor formation and metastasis. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4083. doi:10.1158/1538-7445.AM2015-4083