Abstract 5005: Deletion of bone morphogenetic protein receptor 1A impairs mammary gland development and tumor formation.

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 breast and cancers display active BMP signaling as indicated by phosphorylated Smads 1, 5 and 8. BMP signaling is a known morphogen, responsible for differentiation of many cell types. This led us to hypothesize that BMP signaling may be required for development of the mammary gland and tumors. We first utilized the mammary epithelial specific Cre recombinase driven by the MMTV promoter to remove conditionally floxed BMPR1a alleles. We found that mice lacking BMPR1a (cKO) had significant reduction in epithelial branching morphogenesis within the mammary gland. We further analyzed BMPR1a loss in lactating mice using WAP promoter driven Cre, which demonstrated a loss of milk production. We next combined the MMTV.PyVmT oncogene with mice lacking BMPR1a and found this deletion resulted in delayed tumor onset and extended survival significantly (p-value <.001). Furthering these studies, we investigated the morphology of BMPR1a deleted tumors and found a striking loss of luminal characteristics combined with a stromal desmoplasia. Immunofluorescence staining revealed that cKO tumors co-expressed cytokeratins and mesenchymal cell markers such as Vimentin. This indicated that epithelial-to-mesenchymal (EMT) like changes were occurring upon BMPR1a deletion. We performed a DNA microarray on these tumors and found unique changes, which supported a loss of mammary gland differentiation and resulted in EMT-like activation. We next examined human breast tumor cell lines that previously reported the molecular signature response to BMP stimulation and compared them to primary human mammary epithelial cells (HMEC). Comparing signatures, we found that BMP4 stimulation induced unique genes in HMECs compared to tumor cells. Interestingly, transcriptional targets that were absent from tumors and found in normal HMECs included differentiation related genes. These results suggest that BMP signaling is critically deregulated in tumors. In conclusion, we found that loss of the BMP pathway restricts mammary gland development and impairs tumor formation and progression. Citation Format: Philip Owens, Charli R. Bobbitt, Michael W. Pickup, Agnieszka E. Gorska, Sergey V. Novitskiy, Harold L. Moses. Deletion of bone morphogenetic protein receptor 1A impairs mammary gland development and tumor formation. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5005. doi:10.1158/1538-7445.AM2013-5005