Abstract
BackgroundBone morphogenetic proteins (BMPs) have been reported to maintain epithelial integrity and to antagonize the transforming growth factor β (TGFβ)-induced epithelial to mesenchymal transition. The expression of soluble BMP antagonists is dysregulated in cancers and interrupts proper BMP signaling in breast cancer.MethodsIn this study, we mined the prognostic role of BMP antagonists GREMLIN 1 (GREM1) in primary breast cancer tissues using in-house and publicly available datasets. We determined which cells express GREM1 RNA using in situ hybridization (ISH) on a breast cancer tissue microarray. The effects of Grem1 on the properties of breast cancer cells were assessed by measuring the mesenchymal/stem cell marker expression and functional cell-based assays for stemness and invasion. The role of Grem1 in breast cancer-associated fibroblast (CAF) activation was measured by analyzing the expression of fibroblast markers, phalloidin staining, and collagen contraction assays. The role of Grem1 in CAF-induced breast cancer cell intravasation and extravasation was studied by utilizing xenograft zebrafish breast cancer (co-) injection models.ResultsExpression analysis of clinical breast cancer datasets revealed that high expression of GREM1 in breast cancer stroma is correlated with a poor prognosis regardless of the molecular subtype. The large majority of human breast cancer cell lines did not express GREM1 in vitro, but breast CAFs did express GREM1 both in vitro and in vivo. Transforming growth factor β (TGFβ) secreted by breast cancer cells, and also inflammatory cytokines, stimulated GREM1 expression in CAFs. Grem1 abrogated bone morphogenetic protein (BMP)/SMAD signaling in breast cancer cells and promoted their mesenchymal phenotype, stemness, and invasion. Moreover, Grem1 production by CAFs strongly promoted the fibrogenic activation of CAFs and promoted breast cancer cell intravasation and extravasation in co-injection xenograft zebrafish models.ConclusionsOur results demonstrated that Grem1 is a pivotal factor in the reciprocal interplay between breast cancer cells and CAFs, which promotes cancer cell invasion. Targeting Grem1 could be beneficial in the treatment of breast cancer patients with high Grem1 expression.
Highlights
Bone morphogenetic proteins (BMPs) have been reported to maintain epithelial integrity and to antagonize the transforming growth factor β (TGFβ)-induced epithelial to mesenchymal transition
High GREMLIN 1 (GREM1) expression in breast tumors is associated with a poor prognosis BMPs have been reported to maintain epithelial integrity and to antagonize TGFβ-induced epithelial to mesenchymal transition (EMT), an important process for cancer cell invasion and metastasis [5]
We examined the prognostic role of soluble BMP antagonists in primary breast cancer using an in-house and publicly available cohort of 867 untreated lymph nodenegative breast cancer patients
Summary
Bone morphogenetic proteins (BMPs) have been reported to maintain epithelial integrity and to antagonize the transforming growth factor β (TGFβ)-induced epithelial to mesenchymal transition. CAFs are differentiated from quiescent fibroblasts and are associated with increased expression of myofibroblastic markers, such as vimentin, αsmooth muscle actin (αSMA), fibroblast activation protein (FAP), and fibroblast-specific protein 1 (FSP1, known as S100A4) [2]. Tumors, including those from the breast, often display desmoplasia (a fibrillar network) that is mainly caused by CAFs, in that they produce and remodel ECM components, including collagen, fibronectin, and laminin [3]. The BMP antagonist Coco permits a few dormant breast cancer cells to escape the quiescent state imposed by BMP signaling and thereby establish metastases [9]
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