Abstract
BAG3 is an evolutionarily conserved co-chaperone expressed at high levels and has a prosurvival role in many tumor types. The current study reported that BAG3 was induced under specific floating culture conditions that enrich breast cancer stem cell (BCSC)-like cells in spheres. Ectopic BAG3 overexpression increased CD44+/CD24− CSC subpopulations, first-generation and second-generation mammosphere formation, indicating that BAG3 promotes CSC self-renewal and maintenance in breast cancer. We further demonstrated that mechanically, BAG3 upregulated CXCR4 expression at the post-transcriptional level. Further studies showed that BAG3 interacted with CXCR4 mRNA and promoted its expression via its coding and 3′-untranslational regions. BAG3 was also found to be positively correlated with CXCR4 expression and unfavorable prognosis in patients with breast cancer. Taken together, our data demonstrate that BAG3 promotes BCSC-like phenotype through CXCR4 via interaction with its transcript. Therefore, this study establishes BAG3 as a potential adverse prognostic factor and a therapeutic target of breast cancer.
Highlights
BAG3 is a member of the human BAG co-chaperone family (BAG1–6), which interact with heat-shock protein 70 (HSP70).[1]
Immunoblot analysis of lysates obtained from surgical samples of 10 breast cancer patients confirmed increases of BAG3 expression in most tumors compared with corresponding peritumor tissues (Figure 1c)
BAG3 expression was evaluated by immunohistochemical analysis in 144 breast cancer specimens and confirmed that BAG3 expression was significantly increased in most tumor specimens relative to peritumor tissues (Figure 1d)
Summary
BAG3 is a member of the human BAG co-chaperone family (BAG1–6), which interact with heat-shock protein 70 (HSP70).[1] BAG3 has been assigned to play multiple cellular processes such as autophagy, cell survival, cytoskeleton arrangement, cellular stress response and virus replication.[2,3]. BAG3 expression is stimulated by multiple stressful and physiological stimuli in various normal cells,[2,4,5,6,7,8] and inducible. BCSCs are classically defined CD44 positive and low or absent levels of CD24 expression (CD44+/CD24−/low), and mammosphere cultures have been used to identify BCSC-like subpopulation enriched in CD44+/CD24− /low cells.[27,28]. We showed that BAG3 was induced under specific floating culture conditions that enrich BCSC-like cells in spheres as compared with standard culture condition
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