Abstract
BackgroundTamoxifen resistance remains a clinical challenge for hormone receptor-positive breast cancer. Recently, dysregulations in autophagy have been suggested as a potential mechanism for tamoxifen resistance. Although the long noncoding RNA H19 is involved in various stages of tumorigenesis, its role in tamoxifen resistance remains unknown. Here, we assessed the role of H19 in the development of tamoxifen-resistant breast cancer.MethodsQuantitative real-time PCR analyzed expression of H19 in tamoxifen-resistant breast cancer tissues. Knockdown of H19 was used to assess the sensitivity to tamoxifen in vitro and in vivo. Both knockdown and overexpression of H19 were used to analyze the status of autophagy. Real-time quantitative methylation-specific polymerase chain reaction, chromatin immunoprecipitation, immunofluorescence, and Western blot were used to explore the tamoxifen resistance mechanism of H19.ResultsIn this study, we observed that the expression of H19 was substantially upregulated in tamoxifen-resistant breast cancer cell line and tumor tissues, and knockdown of H19 enhanced the sensitivity to tamoxifen both in vitro and in vivo. Furthermore, knockdown of H19 significantly inhibited autophagy in MCF7 tamoxifen-resistant (MCF7/TAMR) cells. Conversely, overexpression of H19 promoted autophagy. Interestingly, overexpression of H19 in MCF7 tamoxifen-sensitive cells could recapitulate tamoxifen resistance. Moreover, an increase in methylation in the promoter region of Beclin1 was observed in MCF7/TAMR-shH19 cells. In the double knockdown groups, both shH19+shSAHH and shH19+shDNMT3B rescued the Beclin1 promoter region methylation levels and reactivated autophagy functions. A chromatin immunoprecipitation assay further validated that DNMT3B binds to the Beclin1 promoter region and the knockdown of H19 increases this binding.ConclusionsOur findings demonstrate that H19 induces autophagy activation via the H19/SAHH/DNMT3B axis, which could contribute to tamoxifen resistance in breast cancer.
Highlights
Tamoxifen resistance remains a clinical challenge for hormone receptor-positive breast cancer
We showed that Long noncoding RNAs (lncRNAs) H19 (H19) promoted tamoxifen resistance in estrogen receptor (ER)-positive breast cancer cells and autophagy, which occurs via downregulation of methylation in the promoter of Beclin1 by the H19/S-adenosylhomocysteine hydrolase (SAHH)/DNA methyltransferase 3B (DNMT3B) axis
Autophagy facilitates tamoxifen resistance in breast cancer cell lines To investigate the role of autophagy in the development of tamoxifen resistance, we established a tamoxifen-resistant MCF7 cell line (MCF7/Tamoxifen-resistant MCF7 cell line (TAMR)) by culturing a tamoxifen-sensitive MCF7 cell line in medium with 1 μM tamoxifen for over 6 months, as previously described [30, 31]
Summary
Tamoxifen resistance remains a clinical challenge for hormone receptor-positive breast cancer. Dysregulations in autophagy have been suggested as a potential mechanism for tamoxifen resistance. We assessed the role of H19 in the development of tamoxifenresistant breast cancer. 70% of breast cancer patients are estrogen receptor (ER)-positive. Recent studies have shown that autophagy is a potential mechanism for tamoxifen resistance. Overexpression of Beclin, the key mediator of autophagy, desensitizes estrogen-induced signaling, contributing to the development of tamoxifen resistance in ER-positive breast cancers [10]. Inhibition of autophagy genes, such as atg, atg, and Beclin, results in resensitization of tamoxifenresistant breast cancer cells [11, 12]. The underlying mechanism by which autophagy mediates tamoxifen resistance in breast cancer remains to be elucidated
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
