Hypoxia-mediated translational activation of ITGB3 in breast cancer cells enhances TGF-β signaling and malignant features in vitro and in vivo

Abstract

Breast cancer is the most prevalent malignancy in women and there is an urgent need for new therapeutic drugs targeting aggressive and metastatic subtypes, such as hormone-refractory triple-negative breast cancer (TNBC). Control of protein synthesis is vital to cell growth and tumour progression and permits increased resistance to therapy and cellular stress. Hypoxic cancer cells attain invasive and metastatic properties and chemotherapy resistance, but the regulation and role of protein synthesis in this setting is poorly understood. We performed a polysomal RNA-Seq screen in non-malignant breast epithelial (MCF10A) and TNBC (MDA-MB-231) cells exposed to normoxic or hypoxic conditions and/or treated with an mTOR pathway inhibitor. Analysis of both the transcriptome and the translatome identified mRNA transcripts translationally activated or repressed by hypoxia in an mTOR-dependent or -independent manner. Integrin beta 3 (ITGB3) was translationally activated in hypoxia and its knockdown increased apoptosis and reduced survival and migration, particularly under hypoxic conditions. Moreover, ITGB3 was required for sustained TGF-β pathway activation and for the induction of Snail and associated epithelial-mesenchymal transition markers. ITGB3 downregulation significantly reduced lung metastasis and improved overall survival in mice. Collectively, these data suggest that ITGB3 is translationally activated in hypoxia and regulates malignant features, including epithelial-mesenchymal transition and cell migration, through the TGF-β pathway, revealing a novel angle for the treatment of therapy-resistant hypoxic tumours.

Down syndrome iPSC model: endothelial perspective on tumor development

“…Additionally, the positive feedback loops that EDN1, ITGB3, and F3 share with inflammatory genes, such as IL-8, CXCL-1 (GRO-1), IL-33, CCL2, IL-6, and IL-1β, further emphasizes the significant role of this select gene set in angiogenesis. EDN1, ITGB3, and F3 have been implicated in tumor progression [70][71][72], but they have not been well studied with respect to DS. Their down-regulated expression, as shown in our DSV-iECs, also supports the potential presence of an anti-angiogenic microenvironment that may prevent solid tumor growth.…”

MicroRNA-Based Combinatorial Cancer Therapy: Effects of MicroRNAs on the Efficacy of Anti-Cancer Therapies

“…For instance, it was noted that the translational activation of integrin subunit β 3 (ITGB3) supports TGF-β pathways and advances malignant phenotypes, such as EMT. Thus, targeting integrins with antibodies has been attempted for cancer therapy [155,156]. A recent study of miR-483-3p indicated that this miRNA enhances the effectiveness of gefitinib by targeting ITGB3 [154] (Table 5).…”

MicroRNAs, Hypoxia and the Stem-Like State as Contributors to Cancer Aggressiveness

“…Additionally, TNBC cells can grow, survive, induce metabolic reprogramming and apoptosis, alter cell adhesion and motility to facilitate metastasis and resistance to chemotherapy under hypoxic conditions (Semenza, 2001; Muz et al, 2015). A study done using (MDA-MB-231) TNBC cells showed a translational activation of Integrin beta 3 (ITGB3) under hypoxia and that ITGB3 regulated malignant features, including EMT and cell migration, through the TGF-β pathway (Sesé et al, 2017). Also, hypoxia has been shown to represses the expression of many DNA repair genes including the tumor suppressor gene – BRCA1, which has the important role in preventing the formation of breast cancer (Scanlon and Glazer, 2015).…”