Tamoxifen-resistant breast cancer cells are resistant to DNA-damaging chemotherapy because of upregulated BARD1 and BRCA1

Zhu, Yingting; Liu, Yujie; Zhang, Chao; Chu, Jianping; Wu, Yanqing; Li, Yudong; Liu, Jieqiong; Li, Qian; Li, Shunying; Shi, Qingli; Jin, Liang; Zhao, Jianli; Ding, Yin; Efroni, Sol; Su, Fengxi; Yao, Herui; Song, Erwei; Liu, Qiang

doi:10.1038/s41467-018-03951-0

Cited by 113 publications

(102 citation statements)

References 40 publications

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“…However, the differences in colony formation between MDA‐MB‐468 and MDA‐MB‐231 cells after 4 Gy were not significant 30 . It was recently reported that PI3K/AKT inhibitor inhibited the resistance to endocrine or DNA‐damaging radiotherapy in ER‐positive early patients with BC 31 . Besides, activation of the AKT pathway might also contribute to the radioresistance in BC and glioblastoma cells 13,26 .…”

Section: Discussionmentioning

confidence: 97%

CPNE1 predicts poor prognosis and promotes tumorigenesis and radioresistance via the AKT singling pathway in triple‐negative breast cancer

Shao

Zhang³

et al. 2020

Molecular Carcinogenesis

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Elevated expression of Copine 1 (CPNE1) has been observed in multiple cancers; however, the underlying mechanisms by which it affects cancer cells are unclear. We aimed to study the effect of CPNE1 on the tumorigenesis and radioresistance of triple‐negative breast cancer (TNBC). Quantitative real‐time polymerase chain reaction was used to detect the expression of CPNE1 in TNBC tissues and cell lines. Western blot, immunohistochemistry, and immunofluorescence were used to investigate the levels of CPNE1, p‐AKT, AKT, cleaved caspase‐3, cleaved PARP1, and γ‐H2AX. Cell viability and apoptosis were measured by CCK‐8 and flow cytometry, respectively. CPNE1 was overexpressed in TNBC tissues and cell lines and was associated with tumor size, distant metastases, and survival rates of patients with TNBC. Moreover, function study shows that CPNE1 promoted cell viability and inhibited cell apoptosis in vitro and inhibited the radiosensitivity of TNBC. Importantly, inactivation of AKT signaling inhibited the tumorigenesis and radioresistance mediated by CPNE1 in TNBC cells. In vivo xenograft study also shows that CPNE1 knockdown inhibited tumor growth and promoted cell apoptosis. Overall, our findings suggest that CPNE1 promotes tumorigenesis and radioresistance in TNBC by regulating AKT activation and targeted CPNE1 expression may be a strategy to sensitize TNBC cells toward radiation therapy.

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Section: Discussionmentioning

confidence: 97%

CPNE1 predicts poor prognosis and promotes tumorigenesis and radioresistance via the AKT singling pathway in triple‐negative breast cancer

Shao

Zhang³

et al. 2020

Molecular Carcinogenesis

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“…Hormonal therapy and Her2-targeted monoclonal antibodies have significantly improved the clinical outcome of ER + and Her2 + breast cancer (3,4). However, the relatively low response rate and the development of resistance during treatment limits their therapeutic efficacy in numerous ER + or Her2 + breast cancer patients (5,6). The treatment of TNBC patients depends solely on chemotherapy, which reduces the overall survival rate (7).…”

Section: Introductionmentioning

confidence: 99%

Long non‑coding RNA SNHG1 promotes breast cancer progression by regulation of LMO4

Xiong

Feng

et al. 2020

Oncol Rep

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Long non-coding RNA (lncRNA) small nucleolar RNA host gene 1 (SNHG1) was reported to be a critical regulator of tumorigenesis and is frequently deregulated in several cancer types. However, the exact mechanism by which SNHG1 contributes to breast cancer progression has not been fully elucidated. The identification of the molecular mechanism of SNHG1 is important for understanding the development of breast cancer and for improving the prognosis of the patients with this disease. In the present study, increased expression levels of SNHG1 were noted in breast cancer tumors following analysis of differentially expressed lncRNAs between 1,063 tumor and 102 normal tissues derived from The Cancer Genome Atlas Breast Invasive Carcinoma (TCGA-BRCA) dataset. This finding was further validated using 50 pairs of normal and tumor tissues that were collected from patients with breast cancer. Notably, SNHG1 expression was significantly correlated with estrogen receptor (ER)/progesterone receptor (PR) negative status (ER -/PR -) and advanced clinical stage in breast cancer tissues. Knockdown of SNHG1 led to cell growth arrest, cell cycle redistribution and cell migration inhibition of breast cancer cells. The miRDB database predicted that miR-573 interacts with SNHG1. RT-PCR confirmed the negative regulation of miR-573 levels by SNHG1 in breast cancer cells and the Dual-luciferase reporter assay confirmed their complementary binding. The repression of miR-573 by SNGH1 decreased LIM domain only 4 (LMO4) mRNA and protein expression levels in the breast cancer cell lines tested and induced the expression of cyclin D1 and cyclin E. In vitro experiments indicated that LMO4 overexpression could reverse siSNHG1-induced cell growth arrest, cell cycle redistribution and inhibition of cell migration in breast cancer cells. Moreover, the tumor xenograft model indicated that SNHG1 knockdown inhibited MDA-MB-231 growth in vivo and LMO4 overexpression reversed the tumor growth inhibition induced by SNHG1 knockdown. The present study demonstrated that SNHG1 acts as a novel oncogene in breast cancer via the SNHG/miR-573/LMO4 axis and that it could be a promising therapeutic target for patients with breast cancer.

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“…Finally, eIF4E might confer tamoxifen resistance via oestrogen receptor independent pathway due to the activity of mTOR and MNK1 [28], one of the downstream modulators being RUNX2 [33] which is found to be important in breast tumour growth and metastasis [34,35]. Moreover, RUNX2 could regulate the WNT/β-catenin and TCF-β signalling pathways, two pathways essential to tamoxifen resistance [36,37]. In tamoxifen-resistant cells, these mechanisms might work together, forming a single or Our study which demonstrates phosphorylation independent eIF4E translational reprogramming of selective mRNAs determining tamoxifen resistance is novel.…”

Section: Discussionmentioning

confidence: 99%

Phosphorylation independent eIF4E translational reprogramming of selective mRNAs determines tamoxifen resistance in breast cancer

et al. 2020

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Eukaryotic translation initiation factor 4E (eIF4E) selectively promotes translation of mRNAs with atypically long and structured 5′-UTRs and has been implicated in drug resistance. Through genome-wide transcriptome and translatome analysis we revealed eIF4E overexpression could promote cellular activities mediated by ERα and FOXM1 signalling pathways. Whilst eIF4E overexpression could enhance the translation of both ERα and FOXM1, it also led to enhanced transcription of FOXM1. Polysome fractionation experiments confirmed eIF4E could modulate the translation of ERα and FOXM1 mRNA. The enhancement of FOXM1 transcription was contingent upon the presence of ERα, and it was the high levels of FOXM1 that conferred Tamoxifen resistance. Furthermore, tamoxifen resistance was conferred by phosphorylation independent eIF4E overexpression. Immunohistochemistry on 134 estrogen receptor (ER + ) primary breast cancer samples confirmed that high eIF4E expression was significantly associated with increased ERα and FOXM1, and significantly associated with tamoxifen resistance. Our study uncovers a novel mechanism whereby phosphorylation independent eIF4E translational reprogramming in governing the protein synthesis of ERα and FOXM1 contributes to anti-estrogen insensitivity in ER + breast cancer. In eIF4E overexpressing breast cancer, the increased ERα protein expression in turn enhances FOXM1 transcription, which together with its increased translation regulated by eIF4E, contributes to tamoxifen resistance. Coupled with eIF4E translational regulation, our study highlights an important mechanism conferring tamoxifen resistance via both ERα dependent and independent pathways.

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Tamoxifen-resistant breast cancer cells are resistant to DNA-damaging chemotherapy because of upregulated BARD1 and BRCA1

Cited by 113 publications

References 40 publications

CPNE1 predicts poor prognosis and promotes tumorigenesis and radioresistance via the AKT singling pathway in triple‐negative breast cancer

CPNE1 predicts poor prognosis and promotes tumorigenesis and radioresistance via the AKT singling pathway in triple‐negative breast cancer

Long non‑coding RNA SNHG1 promotes breast cancer progression by regulation of LMO4

Phosphorylation independent eIF4E translational reprogramming of selective mRNAs determines tamoxifen resistance in breast cancer

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