High TNFRSF12A level associated with MMP-9 overexpression is linked to poor prognosis in breast cancer: Gene set enrichment analysis and validation in large-scale cohorts

Abstract

BackgroundMatrix metalloproteinase-9 (MMP-9) is associated with remodelling of the extracellular matrix and invasion in various cancers. Identifying proteins connected to high MMP-9 expression is important in explaining its mechanisms. Our study aims to shed light on genes associated with high MMP-9 expression and discuss their clinical impact in breast cancer.MethodsWe evaluated 173 breast cancer cases from the Kangbuk Samsung Hospital, with 1964 cases from the Molecular Taxonomy of Breast Cancer International Consortium database serving as a validation cohort. We investigated relationships between MMP-9 expression and clinicopathological characteristics. We then used gene set enrichment analyses to detect the association of genes with MMP-9 overexpression, and performed survival analyses to determine the significance of the gene in three independent cohorts.ResultsHigh MMP-9 expression correlated with poor prognosis in univariate and multivariate analyses. Using gene set enrichment analysis, we found that tumour necrosis factor receptor superfamily member 12A (TNFRSF12A) was linked to high MMP-9 expression. In the survival analysis of three published data sets (METABRIC, GSE1456, GSE20685), high TNFRSF12A was relevant to a poor survival rate.ConclusionsHigh levels of TNFRSF12A associated with MMP-9 overexpression may be important to explain the progression of breast cancer, and survival could be improved using therapy targeting TNFRSF12A.

EMMPIRRIN(CD147) and matrix matrix metalloproteinase-9 (MMP9) immunohistochemical expression in breast carcinoma: relationship with clinicopathological paremeters

“…In accordance to Yang et al, 2018, this study revealed a significant relation between MMP9 expression and staging. However, there was no significant relation between MMP9 and grading in this study.…”

Prognostic role of matrix metalloproteinase 9 in early breast cancer

“…MMPs are secreted in the form of inactive proenzymes, whose activation is mediated via different molecular mechanisms ( 20 , 21 ). Thus, the level of active MMP9 in stromal cells and tumor cells may vary, which will subsequently account for the differences in clinical outcomes ( 50 ).…”

Hypermethylation of RAD9A intron 2 in childhood cancer patients, leukemia and tumor cell lines suggest a role for oncogenic transformation

“…High PRKD1 mRNA levels have been associated with low overall survival in TNBC (triple-negative breast cancer) [40]. TNFRS12A, also located in the 16p13.3 duplication, is responsible for poor prognosis in breast cancer, if overexpressed [41]. Although the results indicate some tumor-related methylation values of RAD9A, the relationship between tumor type, survival and RAD9A hypermethylation demands larger patients studies.…”