Reciprocal Regulation of DUSP9 and DUSP16 Expression by HIF1 Controls ERK and p38 MAP Kinase Activity and Mediates Chemotherapy-Induced Breast Cancer Stem Cell Enrichment

Abstract

Triple-negative breast cancer (TNBC) has a poor prognosis due to its aggressive characteristics and lack of targeted therapies. Cytotoxic chemotherapy may reduce tumor bulk, but leaves residual disease due to the persistence of chemotherapy-resistant breast cancer stem cells (BCSC), which are critical for tumor recurrence and metastasis. Here, we demonstrate that hypoxia-inducible factor (HIF)-1-dependent regulation of mitogen-activated protein kinase (MAPK) signaling pathways contributes to chemotherapy-induced BCSC enrichment. Chemotherapy increased DUSP9 expression and decreased DUSP16 expression in a HIF1-dependent manner, leading to inhibition of ERK and activation of p38 signaling pathways, respectively. Inhibition of ERK caused transcriptional induction of the pluripotency factor Nanog through decreased inactivating phosphorylation of FoxO3, while activation of p38 stabilized Nanog and Klf4 mRNA through increased inactivating phosphorylation of RNA-binding protein ZFP36L1, both of which promoted specification of the BCSC phenotype. Inhibition of HIF1 or p38 signaling blocked chemotherapy-induced pluripotency factor expression and BCSC enrichment. These surprising results delineate a mechanism by which a transcription factor switches cells from ERK to p38 signaling in response to chemotherapy and suggest that therapeutic targeting of HIF1 or the p38 pathway in combination with chemotherapy will block BCSC enrichment and improve outcome in TNBC. These findings provide a molecular mechanism that may account for the increased relapse rate of women with TNBC who are treated with cytotoxic chemotherapy and suggest that combining chemotherapy with an inhibitor of HIF1 or p38 activity may increase patient survival. .

Convergent evolution of p38/MAPK activation in hormone resistant prostate cancer mediates pro-survival, immune evasive, and metastatic phenotypes

“…Therefore, tumor cells undergoing a stress response independent of enzalutamide or prostate cancer may also rely on p38 activation to persist and survive in ecologically-unfavorable environments, such as the hostile environment of the bloodstream during dissemination, or during treatments that target other oncogenic drivers across different cancer types. For example, p38 activity has been shown in both breast and lung cancer to promote chemotherapy resistance (Flem-Karlsen et al, 2019; Liu et al, 2016; Lu et al, 2018). Activation of p38 has also been linked to DNA repair (Canovas et al, 2018), which is also enriched in our models of enzalutamide resistance (Fig.…”

Cancer stem cells (CSCs) in cancer progression and therapy

“…It is also important to note that chemotherapeutic agent when encounter a hypoxic condition could diversely cause CSC enrichment through regulation mitogen‐activated protein kinase signaling. This regulation is mediated by the inhibition of ERK and activation of p38 signaling for respective induction and stabilization of pluripotency factors in the CSCs (Lu et al, ). Radiotherapy also indirectly induces expression of HIF‐1α (X. Chen et al, ).…”

“…Hypoxia is known as a common feature of the TME (Lan et al, 2018) that is induced diversely after treatment with chemo/radiotherapy (Dianat-Moghadam et al, 2018). Hypoxia is associated with F I G U R E 5 Targeting cancer stem cells (CSCs) for cancer therapies.…”

Microenvironmental Regulation of Long Noncoding RNA LINC01133 Promotes Cancer Stem Cell-Like Phenotypic Traits in Triple-Negative Breast Cancers

“…In similar contexts, KLF4‐miR‐206 signaling, which suppressed pro‐apoptotic PDCD4 and CX43, was essential for the survival of CSC cells derived from established TNBC cell lines as well as in PROCR + /ESA + /ALDH + CSC‐like cells derived from C3(1)/Tag basal/TNBC tumors . KLF4 was also found to play supporting roles in the propagation of CSCs in resurging TNBC growths following chemotherapy administration . Our findings that LINC01133 plays critical upstream regulatory roles of KLF4 expression, together with its enrichment in lineage‐negative CSC‐rich breast tumors (Supporting Information Fig.…”