Isoproterenol-induced Upregulation of HPSE Accelerates Triple-negative Breast Cancer Cell Proliferation and Migration through Enhancing the Transcriptional Activity of HIF-1α.

Abstract

Triple-negative breast cancer (TNBC) is considered to be the most malignant subtype of breast cancer (BC). Heparanase (HPSE) has been reported to contribute to tumor development, but its potential function in TNBC is not clear. The intention of this study was to investigate whether HPSE affects TNBC progression and to explore the possible mechanisms. Bioinformatics analyses were applied to analyze the expression of HPSE in TNBC samples and normal breast samples. The mRNA and protein levels of HPSE in TNBC cells were detected by RT-qPCR and western blot. Function assays, including CCK-8 assay, colony formation assay, transwell assay and wound healing assay, were conducted to validate the effects of HPSE silencing on TNBC cell proliferation and migration. Mechanism experiments were performed to explore the upstream molecular mechanism of HPSE in TNBC cells. Silencing of HPSE suppressed the proliferation and migration of TNBC cells. Moreover, hypoxia-inducible factor-1 alpha (HIF-1α) interacted with the HPSE promoter and promoted the transcription of HPSE. Isoproterenol (ISO), a pharmacological substitute for chronic stress-induced sympathetic activation, was proven to induce HIF-1α upregulation, so as to transcriptionally activate HPSE in TNBC cells. Furthermore, it manifested that ISO facilitated TNBC cell proliferation and migration in an HPSE-dependent way. HPSE activated by ISO-induced HIF-1α promoted TNBC cell proliferation and migration, which might offer a novel insight for TNBC treatment.