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Updated: Jan 19, 2026
Studying TGF-β Signaling and TGF-β-induced Epithelial-to-mesenchymal Transition in Breast Cancer and Normal Cells
Published on: October 27, 2020
Cancer-associated fibroblast-derived Gremlin 1 promotes breast cancer progression
Jiang Ren1, Marcel Smid2, Josephine Iaria3
1Department of Cell and Chemical Biology, Oncode Institute, Leiden University Medical Center, Einthovenweg 20, 2333 ZC, Leiden, The Netherlands.
Background:
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. The expression of soluble BMP antagonists is dysregulated in cancers and interrupts proper BMP signaling in breast cancer.
Methods:
In 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.
Results:
Expression 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.
Conclusions:
Our 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.
Insights
Gremlin 1 (GREM1) promotes breast cancer invasion by fostering communication between cancer cells and fibroblasts. Targeting GREM1 may offer a new therapeutic strategy for patients with high GREM1 expression.
Area of Science:
- Oncology
- Cancer Biology
- Molecular Signaling
Background:
- Bone morphogenetic proteins (BMPs) are known to maintain epithelial integrity and counteract TGFβ-induced epithelial-to-mesenchymal transition.
- Dysregulated BMP antagonist expression, particularly in breast cancer, disrupts crucial BMP signaling pathways.
Purpose of the Study:
- To investigate the prognostic significance of the BMP antagonist Gremlin 1 (GREM1) in primary breast cancer.
- To elucidate the role of GREM1 in breast cancer cell properties and cancer-associated fibroblast (CAF) activation.
- To examine GREM1's impact on breast cancer cell intravasation and extravasation.
Main Methods:
- Analysis of GREM1 expression in breast cancer tissues and cell lines.
- In situ hybridization (ISH) to determine GREM1 RNA localization.
- Functional assays assessing cancer cell stemness, invasion, and CAF activation (fibroblast markers, collagen contraction).
- Zebrafish xenograft models to study intravasation and extravasation.
Main Results:
- High GREM1 expression in breast cancer stroma correlates with poor prognosis across molecular subtypes.
- GREM1 is primarily expressed by breast cancer-associated fibroblasts (CAFs), stimulated by TGFβ and inflammatory cytokines.
- GREM1 enhances breast cancer cell mesenchymal phenotype, stemness, and invasion by inhibiting BMP/SMAD signaling.
- GREM1 promotes CAF activation and facilitates cancer cell intravasation and extravasation in vivo.
Conclusions:
- GREM1 acts as a key mediator in the crosstalk between breast cancer cells and CAFs, driving cancer cell invasion.
- Targeting GREM1 presents a potential therapeutic avenue for breast cancer patients with elevated GREM1 levels.
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