Inhibitory role of large intergenic noncoding RNA-ROR on tamoxifen resistance in the endocrine therapy of breast cancer by regulating the PI3K/Akt/mTOR signaling pathway.

Breast cancer (BC) is the second-leading cause of central nervous system metastases among severe malignancies. This study aimed at investigating the underlying mechanism by which large intergenic noncoding RNA-regulator of reprogramming (lincRNA-ROR) affects the tamoxifen (TAM) resistance of BC cells by regulating the PI3K/Akt/mTOR signaling pathway. Immortalized human mammary epithelial cell line (MCF10A) and BC cell lines (MCF-7, MDA-MB-231, T47D, BCAP-37, and ZK-75-1) were cultured, and BC tissues and adjacent normal breast tissues were collected from 152 BC patients. LincRNA-ROR expression in tissues and cells were detected using reverse transcription quantitative polymerase chain reaction. RNA interference was used to silence lincRNA-ROR in MDA-MB-231 cells, and then the cell proliferation and apoptosis were detected by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and annexin-V and propidium iodide (PI) double staining respectively. The expression of apoptosis-related proteins and PI3K/Akt/mTOR signaling pathway-related proteins was measured by performing western blot assay. The BC tissues and cells presented a higher expression of lincRNA-ROR. MAD-MB-231 cells exhibited the highest lincRNA-ROR expression. After lincRNA-ROR silencing, MAD-MB-231 cells showed decreased proliferation, and increased sensitivity to TAM. Besides, the apoptosis-promoting effect of TAM on MAN-MB-231 cells significantly increased. The expression of PI3K/Akt/mTOR signaling pathway-related proteins and the PI3K/Akt/mTOR signaling pathway were repressed by TAM after silencing lincRNA-ROR. Our study demonstrated that silencing lincRNA-ROR could increase the sensitivity of BC MAD-MB-231 cells to TAM by suppressing the activation of P13K/Akt/mTOR signaling pathway.

Lu PW ，Li L ，Wang F ，Gu YT ... -  《-》

Effects of endoplasmic reticulum stress on the autophagy, apoptosis, and chemotherapy resistance of human breast cancer cells by regulating the PI3K/AKT/mTOR signaling pathway.

Zhong JT ，Yu J ，Wang HJ ，Shi Y ，Zhao TS ，He BX ，Qiao B ，Feng ZW ... -  《-》

Silencing long non-coding RNA ROR improves sensitivity of non-small-cell lung cancer to cisplatin resistance by inhibiting PI3K/Akt/mTOR signaling pathway.

Shi H ，Pu J ，Zhou XL ，Ning YY ，Bai C ... -  《-》

YBX1/lncRNA SBF2-AS1 interaction regulates proliferation and tamoxifen sensitivity via PI3K/AKT/MTOR signaling in breast cancer cells.

Y-box binding protein 1 (YBX1) is a multifunctional oncoprotein that can interact with several long non-coding RNAs (lncRNAs) to regulate metastasis in malignancies including breast cancer (BC). In the present study, we demonstrated the association of YBX1 with oncogenic lncRNA SBF2-AS1 (SET-binding factor 2 antisense RNA 1) via PI3K/AKT/mTOR signaling to regulate BC cell proliferation. We further explored the involvement of the YBX1/SBF2-AS1/PI3K/AKT/mTOR axis in the restoration of tamoxifen (TAM) sensitivity. YBX1-SBF2-AS1 association was predicted in silico and verified by RNA immunoprecipitation (RIP)-qPCR assay. Transfection experiments, Real-time RT PCR, Western blots, Phospho AKT/mTOR antibody array kit, and cell proliferation/apoptosis assays were employed to detect the YBX1/SBF2-AS1/ PI3K/AKT/mTOR axis and its effects upon TAM treatment in vitro. We identified that the YBX1 protein specifically binds to lncRNA SBF2-AS1. Our transfection experiments in MCF-7 and MDA-MB-468 cells with SBF2-AS1 silenced or overexpressed YBX1 plasmids, and their negative controls revealed that YBX1 regulates the expression of SBF2-AS1 by forming a positive feedback loop for its activation. We further demonstrated YBX1-SBF2-AS1 association exerts its effects on cell proliferation via PI3K/AKT/mTOR signaling pathway. Furthermore, we observed an increase in TAM sensitivity in BC cells after the knockdown of YBX1-SBF2-AS1 marked by decreased cell proliferation through disruption of the PI3K/AKT/mTOR axis. Our study has identified a novel YBX1/SBF2-AS1/PI3K/AKT/mTOR regulatory axis which may serve as a potential target to improve the effectiveness and efficacy of TAM treatment in BC.

Hussain SA ，Venkatesh T 《-》

Adipocyte-conditioned medium induces tamoxifen resistance by activating PI3K/Akt/mTOR pathway in estrogen receptor-positive breast cancer cells.

Resistance to endocrine therapy is a major clinical challenge in estrogen receptor (ER)-positive breast cancer. Obesity is associated with the clinical response to ER-positive breast cancers; however, the mechanism underlying obesity-induced resistance to endocrine therapy in ER-positive breast cancers remains unclear. In this study, we investigated the molecular mechanisms underlying obesity-induced resistance to tamoxifen (TAM), an anti-estrogen agent, in the ER-positive breast cancer cell line MCF-7 using differentiated adipocyte-conditioned medium (D-CM). Treatment of the cells with D-CM promoted TAM resistance by reducing TAM-induced apoptosis. The expression levels of the ERα target genes were higher in D-CM-treated cells than those in untreated ones. In contrast, when the cells were cultured in the presence of TAM, the expression levels were decreased, with or without D-CM. Moreover, the expression of the markers for cancer stem-like cells (CSCs) and mammosphere formation was enhanced by co-treating with D-CM and TAM, compared with TAM alone. The phosphatidylinositol-3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway was activated in MCF-7 cells by D-CM treatment, even in the presence of TAM. Inhibition of the PI3K/Akt/mTOR pathway decreased the expression levels of the CSC markers, suppressed mammosphere formation, and resensitized to TAM via inducing apoptosis in D-CM-treated cells. These results indicate that the conditioned medium of differentiated adipocytes promoted TAM resistance by inducing the CSC phenotype through activation of the PI3K/Akt/mTOR pathway in ER-positive breast cancer cells. Thus, the PI3K/Akt/mTOR pathway may be a therapeutic target in obese patients with ER-positive breast cancers.

Nakatsuji M ，Fujimori K 《-》