Network-based approach to identify prognosis-related genes in tamoxifen-treated patients with estrogen receptor-positive breast cancer

Abstract

Tamoxifen is an estrogen receptor (ER) antagonist that is most commonly used for the treatment of ER-positive breast cancer. However, tamoxifen resistance remains a major cause of cancer recurrence and progression. Here, we aimed to identify hub genes implicated in the progression and prognosis of ER-positive breast cancer following tamoxifen treatment. Microarray data (GSE9893) for 155 tamoxifen-treated primary ER-positive breast cancer samples were obtained from the Gene Expression Omnibus database. In total, 1,706 differentially expressed genes, including 859 upregulated genes and 847 downregulated genes, were identified between relapse samples and relapse-free samples. Weighted correlation network analysis clustered genes into 13 modules, among which the tan and blue modules were the most significantly related to prognosis. From these two modules, we further identified and validated two prognosis-related hub genes (GRSF1 and MAPT) via survival analysis based on several publicly available datasets. High expression of GRSF1 predicted poor prognosis, whereas MAPT indicated favorable outcomes in ER-positive breast cancer. Using breast cancer cell lines and tissue samples, we confirmed that GRSF1 was significantly upregulated and MAPT was downregulated in the tamoxifen-resistant group compared with the tamoxifen-sensitive group. The prognostic value of GRSF1 and MAPT was also verified in 48 tamoxifen-treated ER-positive breast cancer patients in our hospital. Gene set enrichment analysis suggested that GRSF1 was potentially involved in RNA degradation and cell cycle pathways, while MAPT was strongly linked to immune-related signaling pathways. Taken together, our findings established novel prognostic biomarkers to predict tamoxifen sensitivity, which may facilitate individualized management of breast cancer.

Tau Isoforms: Gaining Insight into MAPT Alternative Splicing

“…Survival analysis from data obtained from publicly available datasets showed that high expression of the MAPT gene predicted favorable outcomes in ER-positive breast cancer [ 105 ]. Breast cancer cell lines and tissue samples confirmed the downregulation of MAPT in tamoxifen-resistant patients compared to the sensitive ones.…”

“…Breast cancer cell lines and tissue samples confirmed the downregulation of MAPT in tamoxifen-resistant patients compared to the sensitive ones. Gene set enrichment analysis strongly linked the MAPT gene to immune-related signaling pathways [ 105 ]. A possible role for Tau in glioblastoma by controlling 3D cell organization and functions via the PI3K/AKT signaling axis has also been recently suggested by Pagano and colleagues [ 106 ].…”

GRSF1 predicts an unfavorable prognosis and promotes tumorigenesis in lung adenocarcinoma based on bioinformatics analysis and in vitro validation

“…GRSF1 is characterized by 3 RNA recognition motif (RRM) domains (which are responsible for RNA-binding), and participates in cancer progression via the mediation of microRNA-mediated gene expression ( 17 , 18 ). Previous research has shown that patients suffering from estrogen receptor–positive breast cancer with high levels of GRSF1 are more resistant to tamoxifen than those patients with low levels of GRSF1 ( 19 ). Notably, GRSF1 has been observed to facilitate the malignant behavior of cervical cancer cells by stimulating cancer-related signal pathways ( 20 , 21 ).…”