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Identified the novel resistant biomarkers for taxane-based therapy for triple-negative breast cancer.

ABSTRACT: Developing treatment strategies for triple-negative breast cancer (TNBC) has become an important clinical challenge. Currently, taxane-based chemotherapy is one of the standard treatments for TNBC. However, determining the key factor of taxane-resistance is urgently in need for clinical treatment for breast cancer. We used GEO data to generate paclitaxel resistance in two basal-like TNBC cell lines (SUM149 and MDA-MB-468). Seventy-one common upregulated differentially expressed genes (DEGs) and 11 downregulated DEGs were found to be related to paclitaxel resistance. By constructing protein-protein interactions, 28 hub proteins with a degree cutoff criterion of ≥1 were found. Nine hub genes (COL4A6, COL4A5, IL6, PDGFA, LPAR1, FYB, IL20, IL18R1 and INHBA) are involved in important signaling pathways. We found that upregulated PDGFA and downregulated COL4A6 were significantly associated with an insensitive response to neoadjuvant paclitaxel-based therapy. A Kaplan-Meier plot was created to check the prognostic values of 11 hub DEGs in terms of recurrence-free survival. High expressions of PDGFA and LAMB3 were correlated with poor recurrence-free survival, while low levels of FYB, IL18R1, and RASGRP1 indicated poorer relapse-free survival. Our results suggest that PDGFA, COL4A6, LPAR1, FYB, COL4A5, and RASGRP1 might be candidate target genes for taxane-based therapy in basal-like TNBC.

SUBMITTER: Chou CW

PROVIDER: S-EPMC8176163 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Triple-negative breast cancer (TNBC) accounts for 10% to 20% of newly diagnosed invasive breast cancer. Finding effective targets for chemotherapy-resistant TNBC has proven difficult in part because of TNBC's molecular heterogeneity. We have previously reported that likely because of the antiapoptotic activity of glucocorticoid receptor (GR) in estrogen receptor (ER)-negative breast epithelial and cancer cells, high GR expression/activity in early-stage TNBC significantly correlates with chemotherapy resistance and increased recurrence. We hypothesized that pretreatment with mifepristone, a GR antagonist, would potentiate the efficacy of chemotherapy in GR+ TNBCs by inhibiting the antiapoptotic signaling pathways of GR and increasing the cytotoxic efficiency of chemotherapy.TNBC cell apoptosis was examined in the context of physiologic glucocorticoid concentrations, chemotherapy, and/or pharmacologic concentrations of mifepristone. We used high-throughput live microscopy with continuous recording to measure apoptotic cells stained with a fluorescent dye and Western blot analysis to detect caspase-3 and PARP cleavage. The effect of mifepristone on GR-mediated gene expression was also measured. TNBC xenograft studies were performed in female severe combined immunodeficient (SCID) mice and tumors were measured following treatment with vehicle, paclitaxel, or mifepristone/paclitaxel.We found that although mifepristone treatment alone had no significant effect on TNBC cell viability or clonogenicity in the absence of chemotherapy, the addition of mifepristone to dexamethasone/paclitaxel treatment significantly increased cytotoxicity and caspase-3/PARP cleavage. Mifepristone also antagonized GR-induced SGK1 and MKP1/DUSP1 gene expression while significantly augmenting paclitaxel-induced GR+ MDA-MB-231 xenograft tumor shrinkage in vivo.These results suggest that mifepristone pretreatment could be a useful strategy for increasing tumor cell apoptosis in chemotherapy-resistant GR+ TNBC.

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Identified the novel resistant biomarkers for taxane-based therapy for triple-negative breast cancer.

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