Background: Although trastuzumab provides significant clinical benefit for HER2-positive breast cancers, responses are limited by the emergence of resistance. Recent evidence suggests that long noncoding RNAs (lncRNAs) play important roles in tumorigenesis and chemoresistance. However, the regulatory mechanism of lncRNAs in trastuzumab resistance is not well established to date. In this research, we identified the differentially expressed lncRNA and investigated its regulatory role in trastuzumab resistance of breast cancer.Methods: LncRNA microarray and qRT-PCR were performed to identify the dysregulated lncRNAs. Transmission electron microscopy, differential ultracentrifugation and qRT-PCR were used to verify the existence of exosomal AFAP1-AS1 (actin filament associated protein 1 antisense RNA 1). Bioinformatics prediction, RNA fluorescence in situ hybridization (RNA-FISH) and immunoprecipitation assays were performed to identify the direct interactions between AFAP1-AS1 and other associated targets, such as AU-binding factor 1 (AUF1) and ERBB2. Finally, a series gain-or loss-functional assays were done to prove the precise role of AFAP1-AS1 in trastuzumab resistance.Results: AFAP1-AS1 was screened out due to its higher expression in trastuzumab-resistant cells compared to sensitive cells. Increased expression of AFAP1-AS1was associate with poorer response and shorter survival time of breast cancer patients. AFAP1-AS1 was upregulated by H3K27ac modification at promoter region, and knockdown of AFAP1-AS1 reversed trastuzumab resistance. Moreover, extracellular AFAP1-AS1 secreted from trastuzumab resistant cells was packaged into exosomes and then disseminated trastuzumab resistance of receipt cells. Mechanically, AFAP1-AS1 was associated with AUF1 protein, which further promoted the translation of ERBB2 without influencing the mRNA level.Conclusion: Exosomal AFAP1-AS1 could induce trastuzumab resistance through associating with AUF1 and promoting ERBB2 translation. Therefore, AFAP1-AS1 level may be useful for prediction of trastuzumab resistance and breast cancer treatment.

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Trastuzumab is commonly used in the treatment of human epidermal growth factor receptor-2 positive (HER-2+) breast cancer, but its efficacy is often limited by the emergence of chemoresistance. Recent studies indicate that exosomes act as vehicles for exchange of genetic cargo between heterogeneous populations of tumor cells, engendering a transmitted drug resistance for cancer development and progression. However, the specific contribution of breast cancer-derived exosomes is poorly understood. In this study, publicly available expression profiling data from breast cancer and bioinformatics analyses were used to screen potential miRNAs in trastuzumab resistance. A series of gain-or loss-functional assays were performed to define the function of miR-567 and ATG5 in trastuzumab resistance and autophagy, both in vitro and in vivo. Our results showed that miR-567 was significantly decreased in trastuzumab-resistant patients compared with responding patients. Moreover, miR-567 was also downregulated in trastuzumab-resistant cells compared with parental cells. Overexpression of miR-567 reversed chemoresistance, whereas silence of miR-567 induced trastuzumab resistance, both in vitro and in vivo. In addition, enhanced miR-567 could be packaged into exosomes, incorporated into receipt cells, suppressing autophagy and reversed chemoresistance by targeting ATG5. To conclude, exosomal miR-567 plays a key role in reversing trastuzumab resistance via regulating autophagy, indicating it may be a promising therapeutic target and prognostic indicator for breast cancer patients.

Obesity and associated chronic inflammation were shown to facilitate breast cancer (BC) growth and metastasis. Leptin, adiponectin, estrogen, and several pro-inflammatory cytokines are involved in the development of obesity-driven BC through the activation of multiple oncogenic and pro-inflammatory pathways. The aim of this study was to assess the reported mechanisms of obesity-induced breast carcinogenesis and effectiveness of conventional and complementary BC therapies. We screened published original articles, reviews, and meta-analyses that addressed the involvement of obesity-related signaling mechanisms in BC development, BC treatment/prevention approaches, and posttreatment complications. PubMed, Medline, eMedicine, National Library of Medicine (NLM), and ReleMed databases were used to retrieve relevant studies using a set of keywords, including “obesity,” “oncogenic signaling pathways,” “inflammation,” “surgery,” “radiotherapy,” “conventional therapies,” and “diet.” Multiple studies indicated that effective BC treatment requires the involvement of diet- and exercise-based approaches in obese postmenopausal women. Furthermore, active lifestyle and diet-related interventions improved the patients’ overall quality of life and minimized adverse side effects after traditional BC treatment, including postsurgical lymphedema, post-chemo nausea, vomiting, and fatigue. Further investigation of beneficial effects of diet and physical activity may help improve obesity-linked cancer therapies.

Qualitative and quantitative visual outcomes of Asian optic neuritis (ON) patients with seropositive myelin oligodendrocyte glycoprotein (MOG) antibodies remain unknown. We retrospectively evaluated a cohort of new-onset ON patients in Shanghai, China between January 2015 and December 2016. Serum MOG and aquaporin-4 (AQP4) antibodies were detected using cell-based assays, and patients were followed-up for at least 6 months. The clinical characteristics and optical coherence tomography (OCT) results were evaluated in the MOG-seropositive optic neuritis (MOG-ON), AQP4-seropositive (AQP4-ON), and double seronegative (Seronegative-ON) patients. Best-corrected visual acuity (BCVA) and peripapillary retinal nerve fiber layer (RNFL) thickness after 6 months of follow-up were compared. Among MOG-ON (n = 49, 64 eyes), AQP4-ON (n = 76, 102 eyes), and Seronegative-ON patients (n = 100, 116 eyes), the percentages of BCVAs better than 0.8 (20/25) at the 6-month visit were 67.19, 19.60, and 72.41%, respectively, which showed no statistical difference between MOG-ON and Seronegative-ON patients (p = 0.198), but were better than the AQP4-ON patients (P = 0.001). The average peripapillary RNFLs measured 6 months after the attack were 58.03 ± 8.73, 64.34 ± 12.88, and 78.12 ± 13.34 μm for the MOG-ON, AQP4-ON, and Seronegative-ON patients, respectively. There was no statistical difference between MOG-ON and AQP4-ON patients (P = 0.089), but both were thinner than Seronegative-ON patients (P = 0.001). The visual acuity in MOG-ON patients was as good as Seronegative-ON patients, whereas the RNFL of the optic nerve head showed a significant thinning as in the AQP4-ON patients.