Elevated GCN5 expression confers tamoxifen resistance by upregulating AIB1 expression in ER-positive breast cancer

AbstractResistance to tamoxifen is a major clinical challenge. Research in recent years has identified epigenetic changes as mediated by dysregulated miRNAs that can possibly play a role in resistance to tamoxifen in breast cancer patients expressing estrogen receptor (ER). We report here elevated levels of EMT markers (vimentin and ZEB1/2) and reduced levels of EMT-regulating miR-200 (miR-200b and miR-200c) in ER-positive breast cancer cells, MCF-7, that were resistant to tamoxifen, in contrast with the naïve parental MCF-7 cells that were sensitive to tamoxifen. Further, we established regulation of c-MYB by miR-200 in our experimental model. C-MYB was up-regulated in tamoxifen resistant cells and its silencing significantly decreased resistance to tamoxifen and the EMT markers. Forced over-expression of miR-200b/c reduced c-MYB whereas reduced expression of miR-200b/c resulted in increased c-MYB We further confirmed the results in other ER-positive breast cancer cells T47D cells where forced over-expression of c-MYB resulted in induction of EMT and significantly increased resistance to tamoxifen. Thus, we identify a novel mechanism of tamoxifen resistance in breast tumor microenvironment that involves miR-200-MYB signaling.

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Functional role of miR-10b in tamoxifen resistance of ER-positive breast cancer cells through down-regulation of HDAC4

BMC Cancer ◽

10.1186/s12885-015-1561-x ◽

2015 ◽

Vol 15 (1) ◽

Cited By ~ 40

Author(s):

Aamir Ahmad ◽

Kevin R. Ginnebaugh ◽

Shuping Yin ◽

Aliccia Bollig-Fischer ◽

Kaladhar B. Reddy ◽

...

Keyword(s):

Breast Cancer ◽

Cancer Cells ◽

Functional Role ◽

Breast Cancer Cells ◽

Tamoxifen Resistance ◽

Down Regulation ◽

Er Positive ◽

Positive Breast Cancer

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Estrogen Receptor (ESR1) mRNA Expression and Benefit From Tamoxifen in the Treatment and Prevention of Estrogen Receptor–Positive Breast Cancer

Journal of Clinical Oncology ◽

10.1200/jco.2010.32.9615 ◽

2011 ◽

Vol 29 (31) ◽

pp. 4160-4167 ◽

Cited By ~ 71

Author(s):

Chungyeul Kim ◽

Gong Tang ◽

Katherine L. Pogue-Geile ◽

Joseph P. Costantino ◽

Frederick L. Baehner ◽

...

Keyword(s):

Breast Cancer ◽

Gene Expression ◽

Estrogen Receptor ◽

Gene Expression Profiling ◽

Expression Profiling ◽

Tamoxifen Resistance ◽

Linear Predictor ◽

Treatment And Prevention ◽

Er Positive ◽

Positive Breast Cancer

Purpose Several mechanisms have been proposed to explain tamoxifen resistance of estrogen receptor (ER) –positive tumors, but a clinically useful explanation for such resistance has not been described. Because the ER is the treatment target for tamoxifen, a linear association between ER expression levels and the degree of benefit from tamoxifen might be expected. However, such an association has never been demonstrated with conventional clinical ER assays, and the ER is currently used clinically as a dichotomous marker. We used gene expression profiling and ER protein assays to help elucidate molecular mechanism(s) responsible for tamoxifen resistance in breast tumors. Patients and Methods We performed gene expression profiling of paraffin-embedded tumors from National Surgical Adjuvant Breast and Bowel Project (NSABP) trials that tested the worth of tamoxifen as an adjuvant systemic therapy (B-14) and as a preventive agent (P-1). This was a retrospective subset analysis based on available materials. Results In B-14, ESR1 was the strongest linear predictor of tamoxifen benefit among 16 genes examined, including PGR and ERBB2. On the basis of these data, we hypothesized that, in the P-1 trial, a lower level of ESR1 mRNA in the tamoxifen arm was the main difference between the two study arms. Only ESR1 was downregulated by more than two-fold in ER-positive cancer events in the tamoxifen arm (P < .001). Tamoxifen did not prevent ER-positive tumors with low levels of ESR1 expression. Conclusion These data suggest that low-level expression of ESR1 is a determinant of tamoxifen resistance in ER-positive breast cancer. Strategies should be developed to identify, treat, and prevent such tumors.

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Exosomal miR-221/222 enhances tamoxifen resistance in recipient ER-positive breast cancer cells

Breast Cancer Research and Treatment ◽

10.1007/s10549-014-3037-0 ◽

2014 ◽

Vol 147 (2) ◽

pp. 423-431 ◽

Cited By ~ 164

Author(s):

Yifang Wei ◽

Xiaofeng Lai ◽

Shentong Yu ◽

Suning Chen ◽

Yongzheng Ma ◽

...

Keyword(s):

Breast Cancer ◽

Cancer Cells ◽

Breast Cancer Cells ◽

Tamoxifen Resistance ◽

Er Positive ◽

Positive Breast Cancer

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miR10a Mediate Tamoxifen Resistance in ER-Positive Breast Cancer Cells Through Down-Regulation of RFPL-3/hTERT

10.21203/rs.3.rs-819836/v1 ◽

2021 ◽

Author(s):

Wei Sun ◽

Wenjie Han ◽

Aiying Li ◽

Youkui Shi

Keyword(s):

Breast Cancer ◽

Cancer Cells ◽

Breast Cancer Cells ◽

Tamoxifen Resistance ◽

Negative Regulator ◽

Luciferase Reporter ◽

Endocrine Treatment ◽

Breast Cancers ◽

Er Positive ◽

Positive Breast Cancer

Abstract Tamoxifen (TAM) is used as a first-line endocrine treatment for estrogen receptor (ER)-positive breast cancers. However, some patients develop TAM resistance after treatment and the role of miRNAs in TAM resistance still unknown. qPCR assay was performed to assess the expression levels of miR10a and RFPL-3 /hTERT. Western blot analysis was used to determine RFPL-3 /hTERT levels. The direct correlation between miR10a and RFPL-3 was verified by dual-luciferase reporter assay. CCK-8 assay and PicoGreen dsDNA quantification assay were applied to determine cell proliferation ability. In this study, we found that miR10a is downregulated in breast cancer with TAM resistance and that low expression of miR10a is associated with poor prognosis. By studying the regulatory mechanism, we found that miR10a functions as a negative regulator of RFPL-3 mRNA by binding the 3’-UTR region and disrupting the interaction between RFPL-3 and hTERT, which inhibits the proliferation of ER-positive breast cancer cells with TAM resistance. Collectively, our study findings indicate that the downregulation of miR10a activates RFPL-3/hTERT and induces tamoxifen resistance in ER-positive breast cancer cells.

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Autoantibodies Specific to ERα are Involved in Tamoxifen Resistance in Hormone Receptor Positive Breast Cancer

Cells ◽

10.3390/cells8070750 ◽

2019 ◽

Vol 8 (7) ◽

pp. 750 ◽

Cited By ~ 1

Author(s):

Angela Maselli ◽

Stefania Parlato ◽

Rossella Puglisi ◽

Carla Raggi ◽

Massimo Spada ◽

...

Keyword(s):

Breast Cancer ◽

Tumor Growth ◽

Cancer Patients ◽

Tamoxifen Resistance ◽

Breast Cancer Patients ◽

Hormone Receptor Positive ◽

Molecular Events ◽

Therapeutic Decisions ◽

Er Positive ◽

Positive Breast Cancer

Tamoxifen resistance is a major hurdle in the treatment of estrogen receptor (ER)-positive breast cancer. The mechanisms of tamoxifen resistance are not fully understood although several underlying molecular events have been suggested. Recently, we identified autoantibodies reacting with membrane-associated ERα (anti-ERα Abs) in sera of breast cancer patients, able to promote tumor growth. Here, we investigated whether anti-ERα Abs purified from sera of ER-positive breast cancer patients could contribute to tamoxifen resistance. Anti-ERα Abs inhibited tamoxifen-mediated effects on cell cycle and proliferation in MCF-7 cells. Moreover, anti-ERα Abs hampered the tamoxifen-mediated reduction of tumor growth in SCID mice xenografted with breast tumor. Notably, simvastatin-mediated disaggregation of lipid rafts, where membrane-associated ERα is embedded, restored tamoxifen sensitivity, preventing anti-ERα Abs effects. In conclusion, detection of serum anti-ERα Abs may help predict tamoxifen resistance and concur to appropriately inform therapeutic decisions concerning hormone therapy in ER-positive breast cancer patients.

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IGF‐1R pathway activation as putative biomarker for linsitinib therapy to revert tamoxifen resistance in ER‐positive breast cancer

International Journal of Cancer ◽

10.1002/ijc.32668 ◽

2019 ◽

Vol 146 (8) ◽

pp. 2348-2359

Author(s):

Dinja T. Kruger ◽

Xanthippi Alexi ◽

Mark Opdam ◽

Karianne Schuurman ◽

Leonie Voorwerk ◽

...

Keyword(s):

Breast Cancer ◽

Tamoxifen Resistance ◽

Pathway Activation ◽

Er Positive ◽

Positive Breast Cancer

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NR4A1 Regulates Tamoxifen Resistance by Suppressing ERK Signaling in ER-Positive Breast Cancer

Cells ◽

10.3390/cells10071633 ◽

2021 ◽

Vol 10 (7) ◽

pp. 1633

Author(s):

Yu Cheon Kim ◽

Clara Yuri Kim ◽

Ji Hoon Oh ◽

Myoung Hee Kim

Keyword(s):

Breast Cancer ◽

Tamoxifen Resistance ◽

Erk Signaling ◽

Tamoxifen Treatment ◽

Loss Of Function ◽

Mcf7 Cells ◽

Er Positive ◽

Tamoxifen Resistant ◽

Positive Breast Cancer

Endocrine therapy is used to treat estrogen receptor (ER)-positive breast cancer. Tamoxifen is effective against this cancer subtype. Nonetheless, approximately 30% of patients treated with tamoxifen acquire resistance, resulting in therapeutic challenges. NR4A1 plays key roles in processes associated with carcinogenesis, apoptosis, DNA repair, proliferation, and inflammation. However, the role of NR4A1 in tamoxifen-resistant ER-positive breast cancer has not yet been elucidated. Here, we propose that NR4A1 is a promising target to overcome tamoxifen resistance. NR4A1 gene expression was downregulated in tamoxifen-resistant MCF7 (TamR) cells compared to that in MCF7 cells. Kaplan-Meier plots were used to identify high NR4A1 expression correlated with increased survival rates in patients with ER-positive breast cancer following tamoxifen treatment. Gain and loss of function experiments showed that NR4A1 restores sensitivity to tamoxifen by regulating cell proliferation, migration, invasion, and apoptosis. NR4A1 localized to the cytoplasm enhanced the expression of apoptotic factors. In silico and in vitro analyses revealed that NR4A1 enhanced responsiveness to tamoxifen by suppressing ERK signaling in ER-positive breast cancer, suggesting that the NR4A1/ERK signaling axis modulates tamoxifen resistance. These results indicate that NR4A1 could be a potential therapeutic target to overcome tamoxifen resistance in ER-positive breast cancer.

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