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

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.

TrkB induced metastatic potential of cancer by suppression of BMP mediated tumor inhibitory activity

“…Furthermore, eradicating the [30,31]. Moreover, Gremlin 1 promotes its stem cell maintenance in glioma and colorectal cancer [32,33], and upregulation of Gremlin 1 significantly correlated with induced stem cell markers and poor survival of estrogen receptor (ER)-negative breast cancer patients [8]. These previous results are conspicuously consistent with our present results.…”

“…Like functions of TGF-β in cancer microenvironments, BMPs and their receptors have implicated an essential role as a dual function, which has a tumor suppressor and promoter of tumor progression in cancer. For example, Gremlin 1 expression, BMP-antagonist, in an analysis of large patient cohorts significantly increased in tumor tissues of breast cancer patients [8]. Also, Gremlin 1 induces tumorigenesis of cancer cells by inhibiting BMP/SMAD signaling and associated poor prognosis of breast cancer patients [9].…”

Identification of Prognostic Model and Biomarkers for Cancer Stem Cell Characteristics in Glioblastoma by Network Analysis of Multi-Omics Data and Stemness Indices

“…Cancer stem cell models derived from 16 acute myeloid leukemia (AML) samples demonstrated an extraordinary ability to predict the clinical outcome of AML (Eppert et al, 2011). Similarly, in breast cancer, colon cancer, gastric cancer, and non-small cell lung cancer, the stem cell gene profile model holds promise in redefining clinical outcome stratification and identifying reduced risk (Giampieri et al, 2013;Miao et al, 2017;Codony-Servat et al, 2019;Neckmann et al, 2019). Moreover, three miRNAs (miR-23a, miR-9-3p, and miR-27a) derived from the analysis of GSCs by gene expression profiling, grouped mesenchymal and proneural GBM patients into two different categories with significant survival differences (Marziali et al, 2017).…”

Association between SNPs within MicroRNA Binding Sites and the Prognosis of Breast Cancer

“…Mutations in LRRK2 gene have been demonstrated to be associated with autosomal-dominant Parkinson's disease [22,23]. Studies have revealed that single nucleotide polymorphism in LRRK2 gene have been related to Crohn's disease [24,25]. It is reported that LRRK2 gene is involved in a variety of cellular processes including cell transformation, proliferation and tumorigenesis, and is linked to various types of cancer [26,27].…”