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Cell Commun Signal. 2019 Nov 6;17(1):140. doi: 10.1186/s12964-019-0467-7.

GREM1 is associated with metastasis and predicts poor prognosis in ER-negative breast cancer patients.

Author information

1
Centre of Molecular Inflammation Research, Department of Clinical and Molecular Medicine, Faculty of Medicine and Health Sciences, NTNU - Norwegian University of Science and Technology, Trondheim, Norway.
2
Department of Biomedical Laboratory Science, Faculty of Natural Sciences, NTNU - Norwegian University of Science and Technology, Trondheim, Norway.
3
Clinic of Laboratory Medicine, St Olavs Hospital, Trondheim, Norway.
4
Department of Biotechnology and Food Science, Faculty of Natural Sciences, NTNU - Norwegian University of Science and Technology, Trondheim, Norway.
5
K.G. Jebsen Center for Genetic Epidemiology, Department of Public Health and General Practice, Faculty of Medicine and Health Sciences, NTNU - Norwegian University of Science and Technology, Trondheim, Norway.
6
Department of Cell and Chemical Biology, Oncode Institute, Leiden University Medical Center, Leiden, The Netherlands.
7
Department of Molecular Oncology, Institute for Cancer Research, Oslo University Hospital-Radiumhospitalet, Oslo, Norway.
8
Department of Informatics, University of Oslo, Oslo, Norway.
9
Department of Clinical and Molecular Medicine (IKOM), NTNU, Gastro Center, Prinsesse Kristinas gt 1, 7030, Trondheim, Norway. toril.holien@ntnu.no.
10
Department of Hematology, St. Olavs Hospital, Trondheim, Norway. toril.holien@ntnu.no.

Abstract

BACKGROUND:

In breast cancer, activation of bone morphogenetic protein (BMP) signaling and elevated levels of BMP-antagonists have been linked to tumor progression and metastasis. However, the simultaneous upregulation of BMPs and their antagonist, and the fact that both promote tumor aggressiveness seems contradictory and is not fully understood.

METHODS:

We analyzed the transcriptomes of the metastatic 66cl4 and the non-metastatic 67NR cell lines of the 4T1 mouse mammary tumor model to search for factors that promote metastasis. CRISPR/Cas9 gene editing was used for mechanistic studies in the same cell lines. Furthermore, we analyzed gene expression patterns in human breast cancer biopsies obtained from public datasets to evaluate co-expression and possible relations to clinical outcome.

RESULTS:

We found that mRNA levels of the BMP-antagonist Grem1, encoding gremlin1, and the ligand Bmp4 were both significantly upregulated in cells and primary tumors of 66cl4 compared to 67NR. Depletion of gremlin1 in 66cl4 could impair metastasis to the lungs in this model. Furthermore, we found that expression of Grem1 correlated with upregulation of several stem cell markers in 66cl4 cells compared to 67NR cells. Both in the mouse model and in patients, expression of GREM1 associated with extracellular matrix organization, and formation, biosynthesis and modification of collagen. Importantly, high expression of GREM1 predicted poor prognosis in estrogen receptor negative breast cancer patients. Analyses of large patient cohorts revealed that amplification of genes encoding BMP-antagonists and elevation of the corresponding transcripts is evident in biopsies from more than half of the patients and much more frequent for the secreted BMP-antagonists than the intracellular inhibitors of SMAD signaling.

CONCLUSION:

In conclusion, our results show that GREM1 is associated with metastasis and predicts poor prognosis in ER-negative breast cancer patients. Gremlin1 could represent a novel target for therapy.

KEYWORDS:

4T1 model; 66cl4; 67NR; BMP4; GREM1; Gremlin 1; Metastasis

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