ABSTRACT
Aberrant leptin signaling and overexpression of fibroblast growth factor receptor 1 (FGFR1) are both implicated in the pathogenesis of letrozole resistance in breast cancer (BCa), but it remains unknown whether these two pathways are involved in letrozole resistance in a coordinated manner. Here, we demonstrate that expression levels of the pre-B-cell leukemia homeobox transcription factor 3 (PBX3), a pioneer factor that governs divergent biological processes, were significantly upregulated in letrozole-resistant BCa cells and tissues, and this upregulation correlated to a poorer progression-free survival in patients. By leveraging a patient-derived xenograft model with pharmacological approaches, we demonstrated that leptin activated PBX3 expression in a STAT3 (signal transducer and activator of transcription 3)-dependent manner. Our loss- and gain-of-function study further showed that PBX3 attenuated response to letrozole by potentiating BCa cell survival and anchorage-independent growth in BCa cells. By profiling BCa cells with ectopic PBX3 expression, we revealed that PBX3 conferred letrozole resistance via transactivation of the FGFR1 signaling, and this molecular event must coordinate a synergistic transcription activation programs through interacting with MTA1-HDAC2 (metastasis associated 1-histone deacetylase 2) complex. Overall, the available data reveal a novel role of leptin/PBX3 cascade linking energy homeostasis (i.e. hyperleptinemia) and endocrine therapy failure (i.e. letrozole resistance) in BCa.
ABSTRACT
BACKGROUND: Breast cancer is a prominent cause of death among women worldwide. Recent studies have demonstrated that artemisinin (ART) displays anti-tumor activity. Using a mouse breast cancer model, we investigated the effects of ART in vitro and in vivo to determine how it influences the anti-tumor immune response. METHODS: We measured the proliferation and apoptosis of 4T1 cells in vitro after ART treatment by MTT assay and FACS. To examine the effects of ART in vivo, tumor volumes and survival rates were measured in 4T1 tumor-bearing mice. FACS was used to determine the frequencies of Tregs, MDSCs, CD4+ IFN-γ+ T cells, and CTLs in the tumors and spleens of the mice. mRNA levels of the transcription factors T-bet and FOXP3 and cytokines IFN-γ, TNF-α, TGF-ß, and IL-10 were also determined by real-time RT-PCR. ELISA was used to measure TGF-ß protein levels in the cell culture supernatants. RESULTS: ART supplementation significantly increased 4T1 cell apoptosis and decreased TGF-ß levels in vitro. ART also impeded tumor growth in 4T1 TB mice and extended their survival. MDSC and Treg frequencies significantly decreased in the 4T1 TB mice after ART treatment while CD4+ IFN-γ+ T cells and CTLs significantly increased. ART significantly increased T-bet, IFN-γ, and TNF-α mRNA levels within the tumor and significantly decreased TGF-ß mRNA levels. CONCLUSION: ART supplementation hindered 4T1 tumor growth in vivo by promoting T cell activation and quelling immunosuppression from Tregs and MDSCs in the tumor.
