Abstract 4001: Gremlin-1 augments the estrogen-related receptor α signaling: Implications for progression of breast cancer in synergistic manner

Gremlin-1 (GREM1), one of the bone morphogenic protein (BMP) antagonists, is known to be involved in organogenesis, tissue differentiation, and pathogenesis of several renal disorders including fibrosis, inflammation, and diabetes. Recently, it has also been reported that aberrant epithelial GREM1 expression initiates colonic tumorigenesis. However, the role of GREM1 in breast cancer remain largely elusive. We observed that GREM1 expression was highly increased in human breast cancer cells and tissues obtained from breast cancer patients. Furthermore, its overexpression is associated with poor prognosis of breast cancer patients, especially those with estrogen receptor (ER)-negative tumors. Suppression of GREM1 expression significantly inhibited the proliferation of SKBR3 human breast cancer cells in culture and xenograft mammary tumor growth while its overexpression enhanced their viability and invasiveness. Estrogen-related receptor α (ERRα) is an orphan nuclear hormone receptor and has recently attracted attention as a novel therapeutic target in the management of triple-negative breast cancers. We observed that ERRα binds directly to GREM1 promoter and modulates GREM1 expression. The mRNA level of GREM1 was reduced by an inverse agonist of ERRα, XCT790 and also by siRNA silencing of ERRα. Conversely, the overexpression of ERRα with its co-factor peroxisome proliferator-activated receptor gamma co-activator 1-α increased the mRNA level of GREM1. Surprisingly, the transcriptional activity of ERRα was found to be regulated by GREM1. The promoter activity of ERRα and the mRNA levels of ERRα target genes were highly increased in GREM1-overexpressing breast cancer cells. Treatment of MCF-7 cells with recombinant GREM1 protein also enhanced the ERRα promoter activity and transcription of its target genes. Taken together, our study identifies for the first time that the GREM1 can act as a downstream signaling molecule of the transcription factor ERRα and suggests a positive feedback loop between ERRα and GREM1, highlighting GREM1 as a potential diagnostic and therapeutic target for the treatment of ER-negative breast cancer. Citation Format: Sin-Aye Park, Bae-Jung Choi, Wonki Kim, Young-Joon Surh. Gremlin-1 augments the estrogen-related receptor α signaling: Implications for progression of breast cancer in synergistic manner [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4001.