GPR116/MMP8 Signaling Pathway Regulates Breast Cancer Growth Through Modulating Tumor-associated Neutrophils Polarization

Breast Cancer is most commonly diagnosed cancer in female, as well as the leading threat for women’s health. Not only carcinogenic mutations of cells but also the tumorigenic microenvironments contribute to breast cancer development and progression. Adhesion G protein-coupled receptors (aGPCRs) have a long extracellular N terminal with various functional domains, and play important roles in regulating cell motility, adhesion and the signal contacts of cell to cell and cell to extracellular environment. Although GPR116, a member of aGPCRs, can promote breast cancer cell invasion and metastasis in our previous study, the effects of GPR116 on breast cancer microenvironment are poorly characterized. Thus, we explored its potential roles in modulating breast cancer microenvironment. First, we found MMP8 was significantly upregulated in GPR116 knock-down breast cancer cell by RNA-seq tests, which was further confirmed through both cell biological assays and transcriptome database analysis of malignant breast cancer patients. Mechanically, we found GPR116 inhibited Erkl/2 phosphorylation and further impaired the level of p-C/EBPβ that was responsible for MMP8 transcription initiation, otherwise upregulation of MMP8 by inhibiting GPR116. More importantly, this regulation process was dependent on nuclear transportation of p-C/EBPβ, which bound to two conserved sequence between 149bp and 53bp at the upstream of MMP8 transcriptional start site. It is widely reported that MMP8 can block breast cancer growth, metastasis and impair paracrine TGF-β signaling. More importantly, the latest research shows that MMP8 have a critical effect on tumor-associated neutrophils infiltration. Similarly,accompanied by upregulation of MMP8 inactivating TGF-β in the tumor microenvironment, GPR116 knock-down suppressed breast cancer initiation and growth through inhibiting the pro-tumorigenic N2-type tumor associated neutrophils. Taken together, our observations provide novel insights into the function of GPR116/MMP8 signaling pathway on modulating breast cancer microenvironment and progression. Thus, GPR116 might be a potential therapeutic target for breast cancer patients.