Deletion of the BMP receptor BMPR1a impairs mammary tumor formation and metastasis

Abstract

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.

TransCONFIRM: Identification of a Genetic Signature of Response to Fulvestrant in Advanced Hormone Receptor–Positive Breast Cancer

“…In this gene set, upregulation of 27 genes was associated with poor PFS. These genes include genes that have known functions in the regulation of the ER transcriptional network (TFAP2C 18, 19 and SP1 20, 21 ), genes that have been shown to be related to breast cancer biology and clinical outcomes (TFAP2C, BMPR1A 22 , ARRDC3 23 , PPP2R3A 24 ) and genes not yet reported to be related to breast cancer but with functional roles in tumorigenesis, metastases and response to treatment in other cancer types and may also have molecular functions in breast cancer (ILF2 25 , ATP11B 26 , CSDA 27 , USP5 28 ,TANC1 29 , NOTCH2 30 , ADD3 31 and SEC23A 32 ). In addition, there are a number of genes in the gene set that do not have known roles in cancer biology (CCDC93, CPNE1, GLTP and TCEB3).…”

Silibinin inhibits ultraviolet B radiation‐induced mast cells recruitment and bone morphogenetic protein 2 expression in the skin at early stages in Ptch(+/−) mouse model of basal cell carcinoma

“…The BMPs roles in cancer are sometimes contradictory since they have been shown to be linked with carcinogenesis and tumor progression though sometimes also appear to act as tumor suppressors . Mostly, BMPs appear to be involved in metastasis, epithelial‐mesenchymal transition, altered cell behavior and angiogenesis in human cancer . In the skin, BMPs appears to play an antitumor role, though the studies so far have been limited to chemical induced skin carcinogenesis models or transgenic mouse models that do not lead to BCCs .…”

Emerging roles of the bone morphogenetic protein pathway in cancer: potential therapeutic target for kinase inhibition

“…In addition, in a tissue microarray analysis, BMPR1B overexpression and SMAD1 phosphorylation were associated with higher tumour grade, more aggressive cancer progression and poorer prognosis [116]. Consistent with the oncogenic role of BMPR1A, in a mouse genetic model expressing MMTV.PyMT oncogene, deletion of BMPR1A impaired mammary tumour formation and metastasis [117]. Finally, treatment with DMH1 reduced lung metastasis in MMTV.PyVmT expressing mice, and the tumours were less proliferative and more apoptotic.…”