Network Analysis Identifies Potential Small-Molecule Drugs Sensitizing Triple-Negative Breast Cancer to Tamoxifen: Small-Molecule Drugs Re-sensitizing TNBC to Tamoxifen

Abstract

Background: Triple-negative breast cancer (TNBC) is the most aggressive type of breast cancer and does not benefit from endocrine therapy targeting the estrogen receptor (ER). Increasing the expression of ER in TNBC cells using pharmacological tools may make endocrine therapy available for the treatment of TNBC. We aimed to identify molecules that may reverse ER expression in TNBC. Methods: The mRNA profiles of breast cancer tissues were downloaded from The Cancer Genome Atlas. The gene modules that were correlated between TNBC and luminal subtype were extracted based on mRNA profiles using weighted gene co-expression network analysis (WGCNA). The Connective Map (CMap) was used to predict small molecular compounds that could reverse the expression levels of hub genes in TNBC. The viability of MDA-MB-231 cells incubated with the combinations of indicated compounds and tamoxifen was determined using Cell Counting Kit-8 and clone formation assays. Results: In total, 3868 differentially expressed genes in breast cancer were analyzed using WGCNA. When the TNBC and luminal subtypes were attributed to specific phenotypes, gene modules derived from the co-expression network were identified. A total of 176 genes that were positively correlated with TNBC and 109 genes that were negatively correlated with TNBC were identified as hub genes. The hub genes in TNBC and the luminal subtype were distinct from each other, and the hub genes in TNBC showed a dysfunction in the cell cycle. CMap analysis demonstrated that GW-8510 was a leading candidate for reversing hub gene expression in TNBC. The upregulation of ER as well as progesterone receptor expression in MDA-MB-231 cells by GW-8510 was verified. Moreover, the combined application of GW-8510 and tamoxifen resulted in a synthetic loss of viability in MDA-MB-231 cells. Conclusion: GW-8510 re-sensitized TNBC to tamoxifen-based hormone therapy, providing a new opportunity for TNBC therapy.