Dexamethasone induces docetaxel and cisplatin resistance partially through up-regulating Krüppel-like factor 5 in triple-negative breast cancer

Abstract

PurposeDexamethasone (Dex), a glucocorticoid (GC), is used as a pretreatment drug in cancer patients undergoing chemotherapy. Dex functions by binding to the glucocorticoid receptor (GR) to prevent allergic reactions and severe chemotherapeutic side effects such as nausea and vomiting. However, the mechanisms by which Dex causes chemoresistance remain unknown.MethodsWe used docetaxel and cisplatin to treat triple-negative breast cancer (TNBC) cells with or without Dex and assessed cell proliferation using a sulforhodamine B colorimetric (SRB) assay. Additionally, Western blotting was employed to measure Krüppel-like factor 5 (KLF5), GR and several apoptosis-related proteins. To determine how the GR regulates KLF5, we used qRT-PCR, luciferase reporter assays and ChIP assays. Finally, we detected the involvement of Dex in TNBC chemotherapeutic resistance using HCC1806 xenograft model in vivo.ResultsIn this study, we demonstrated that Dex induces docetaxel and cisplatin resistance in TNBC cells in vitro and in vivo. Dex up-regulates pro-survival transcription factor KLF5 expression at both mRNA and protein levels dependent on GR. Importantly, Dex failed to promote cancer cell survival and tumor growth when KLF5 induction was blocked.ConclusionsWe conclude that KLF5 is a Dex-induced gene that contributes to Dex-mediated drug chemoresistance, providing a potential novel target for TNBC treatment.

STAT3 and GR cooperate to drive basal-like triple negative breast cancer gene expression and proliferation

“…The study of GR's role in basal-like breast cancer has important clinical implications because potent synthetic glucocorticoids are often prescribed to breast cancer patients undergoing chemotherapy to prevent side-effects such as nausea, loss of appetite, and rare severe immune reactions. Our preliminary data supports a handful of other studies that report that induction of GR with glucocorticoids could promote tumor growth and therapy resistance (15,17,18,52). In our study specifically, it is clear that glucocorticoid induction of GR leads to increased cell proliferation in basal-like breast cancer cell lines and patient-derived organoids.…”

“…The role of many TFs have been studied in basal-like breast cancer, including oncogenic drivers such as MYC (6), and other TFs that regulate pathways associated with basal-like phenotypes such as EN1 (7), GLI1 (8), NF-kB (9), HIF1a (10), TWIST1 (11), FOXC1 (12,13), AP-1 (14), GR (15)(16)(17)(18), STAT3 (19,20), and MAFK (21). Many of these TFs regulate important pathways in basal-like breast cancer and these TFs often regulate each other's expression (22,23).…”

EGFR and Prion protein promote signaling via FOXO3a‐KLF5 resulting in clinical resistance to platinum agents in colorectal cancer

“…High expression levels of KLF5 are a determinant of resistance to cisplatin in ovarian and breast cancers (Dong et al ., ; Li et al ., ) and corresponded with enhanced EGFR signaling in both colorectal cell lines (Fig. C,E).…”

“…A,B). KLF5 typically supports proliferation in nontransformed cells, providing a growth advantage (Bateman et al ., ; Chanchevalap et al ., ; Sun et al ., ), and has been shown to induce cisplatin resistance in breast cancer (Li et al ., ). In contrast to these findings, KLF5 has been shown to have growth inhibitory properties in colon cancer‐derived cells (Bateman et al ., ).…”

“…The consequences of reduced signaling resulted in reduced nuclear KLF5. KLF5 is present primarily in the epithelial cells lining the bases of the crypts and has been linked with cisplatin resistance in breast cancer (Li et al ., ). This supports the hypothesis that PrP C serves as a binding partner of EGFR and proto‐oncogene supporting colorectal cell proliferation and response to therapy via control of gene expression.…”