Deletion of the BMP receptor BMPR1a impairs mammary tumor formation and metastasis
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Michael W. Pickup1,*, Laura D. Hover2,*, Yan Guo3,4, Agnieszka E. Gorska4, Anna Chytil4, Sergey V. Novitskiy4, Harold L. Moses4 and Philip Owens4
1 Department of Surgery and Center for Bioengineering and Tissue Regeneration, University of California at San Francisco, San Francisco, CA, USA
2 Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA
3 Vanderbilt Ingram Cancer Center, Center for Quantitative Sciences, Nashville, TN, USA
4 Department of Cancer Biology, Vanderbilt Ingram Cancer Center, Vanderbilt University, Nashville, TN, USA
* These authors contributed equally and should be considered co-first authors
Philip Owens, email:
Keywords: BMPR1a, BMP, breast cancer, EMT, metastasis
Received: April 08, 2015 Accepted: May 27, 2015 Published: June 10, 2015
Bone Morphogenetic Proteins (BMPs) are secreted cytokines/growth factors belonging to the Transforming Growth Factor β (TGFβ) family. BMP ligands have been shown to be overexpressed in human breast cancers. Normal and cancerous breast tissue display active BMP signaling as indicated by phosphorylated Smads 1, 5 and 9. We combined mice expressing the MMTV.PyMT oncogene with mice having conditional knockout (cKO) of BMP receptor type 1a (BMPR1a) using whey acidic protein (WAP)-Cre and found this deletion resulted in delayed tumor onset and significantly extended survival. Immunofluorescence staining revealed that cKO tumors co-expressed Keratin 5 and mesenchymal cell markers such as Vimentin. This indicates that epithelial-to-mesenchymal (EMT)-like transitions occurred in cKO tumors. We performed microarray analysis on these tumors and found changes that support EMT-like changes. We established primary tumor cell lines and found that BMPR1a cKO had slower growth in vitro and in vivo upon implantation. cKO tumor cells had reduced migration in vitro. We analyzed human databases from TCGA and survival data from microarrays to confirm BMPR1a tumor promoting functions, and found that high BMPR1a gene expression correlates with decreased survival regardless of molecular breast cancer subtype. In conclusion, the data indicate that BMP signaling through BMPR1a functions as a tumor promoter.
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