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

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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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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miR-449a Suppresses Tamoxifen Resistance in Human Breast Cancer Cells by Targeting ADAM22

Cellular Physiology and Biochemistry ◽

10.1159/000493964 ◽

2018 ◽

Vol 50 (1) ◽

pp. 136-149 ◽

Cited By ~ 13

Author(s):

Jun Li ◽

Mingjie Lu ◽

Jiao Jin ◽

Xiyi Lu ◽

Tongpeng Xu ◽

...

Keyword(s):

Breast Cancer ◽

Cancer Cells ◽

Breast Cancer Cells ◽

Tamoxifen Resistance ◽

Luciferase Assay ◽

Protein Protein Interaction ◽

Er Positive ◽

Tamoxifen Resistant ◽

Mcf 7 ◽

Positive Breast Cancer

Background/Aims: Most of estrogen receptor positive breast cancer patients respond well initially to endocrine therapies, but often develop resistance during treatment with selective estrogen receptor modulators (SERMs) such as tamoxifen. Altered expression and functions of microRNAs (miRNAs) have been reportedly associated with tamoxifen resistance. Thus, it is necessary to further elucidate the function and mechanism of miRNAs in tamoxifen resistance. Methods: Tamoxifen sensitivity was validated by using Cell Counting Kit-8 in tamoxifen-sensitive breast cancer cells (MCF-7, T47D) and tamoxifen-resistant cells (MCF-7/TAM, T47D/ TAM). Quantitative real-time polymerase chain reaction (qRT-PCR) was performed to detect the expression level of miR-449a in tamoxifen-sensitive/-resistant cells and patient serums. Dual-luciferase assay was used to identify the binding of miR-449a and predicted gene ADAM22. The expression level of ADAM22 was determined by qRT-PCR and western blotting in miR-449a +/- breast cancer cells. Subsequently, rescue experiments were carried out to identify the function of ADAM22 in miR-449a-reduced tamoxifen resistance. Finally, Gene ontology (GO) and Protein-protein interaction analyses were performed to evaluate the potential mechanisms of ADAM22 in regulating tamoxifen resistance. Results: MiR-449a levels were downregulated significantly in tamoxifen-resistant breast cancer cells when compared with their parental cells, as well as in clinical breast cancer serum samples. Overexpression of miR-449a re-sensitized the tamoxifen-resistant breast cancer cells, while inhibition of miR-449a conferred tamoxifen resistance in parental cells. Luciferase assay identified ADAM22 as a direct target gene of miR-449a. Additionally, silencing of ADAM22 could reverse tamoxifen resistance induced by miR-449a inhibition in ER-positive breast cancer cells. GO analysis results showed ADAM22 was mainly enriched in the biological processes of cell adhesion, cell differentiation, gliogenesis and so on. Protein-protein interaction analyses appeared that ADAM22 might regulate tamoxifen resistance through PPARG, LGI1, KRAS and LYN. Conclusion: Decreased miR-449a causes the upregulation of ADAM22, which induces tamoxifen resistance of breast cancer cells. These results suggest that miR-449a, functioning by targeting ADAM22, contributes to the mechanisms underlying breast cancer endocrine resistance, which may provide a potential therapeutic strategy in ER-positive breast cancers.

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Role of AIB1 for Tamoxifen Resistance in Estrogen Receptor-Positive Breast Cancer Cells

Oncology ◽

10.1159/000159267 ◽

2008 ◽

Vol 75 (3-4) ◽

pp. 159-168 ◽

Cited By ~ 26

Author(s):

Qingbo Su ◽

Sanyuan Hu ◽

Haidong Gao ◽

Rong Ma ◽

Qifeng Yang ◽

...

Keyword(s):

Breast Cancer ◽

Estrogen Receptor ◽

Cancer Cells ◽

Breast Cancer Cells ◽

Tamoxifen Resistance ◽

Estrogen Receptor Positive ◽

Positive Breast Cancer

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MLL3 Induced by Luteolin Causes Apoptosis in Tamoxifen-Resistant Breast Cancer Cells through H3K4 Monomethylation and Suppression of the PI3K/AKT/mTOR Pathway

The American Journal of Chinese Medicine ◽

10.1142/s0192415x20500603 ◽

2020 ◽

Vol 48 (05) ◽

pp. 1221-1241 ◽

Cited By ~ 1

Author(s):

Han-Tsang Wu ◽

Yi-En Liu ◽

Kai-Wen Hsu ◽

Yu-Fen Wang ◽

Ya-Chi Chan ◽

...

Keyword(s):

Breast Cancer ◽

Cancer Cells ◽

Breast Cancer Cells ◽

Tamoxifen Resistance ◽

Mtor Inhibitors ◽

Ras Gene ◽

Ras Genes ◽

Er Positive ◽

Tamoxifen Resistant ◽

Positive Breast Cancer

Tamoxifen is one of the most common hormone therapy drug for estrogen receptor (ER)-positive breast cancer. Tumor cells with drug resistance often cause recurrence and metastasis in cancer patients. Luteolin is a natural compound found from various types of vegetables and exhibit anticancer activity in different cancers. This study demonstrated that luteolin inhibits the proliferation and induces apoptosis of tamoxifen-resistant ER-positive breast cancer cells. Luteolin also causes cell cycle arrest at the G2/M phase and decreases mitochondrial membrane potential. Besides, luteolin reduces the levels of activated PI3K/AKT/mTOR signaling pathway. The combination treatment of luteolin and PI3K, AKT, or mTOR inhibitors synergistically increases apoptosis in tamoxifen-resistant ER-positive breast cancer cells. Ras gene family (K-Ras, H-Ras, and N-Ras), an activator of PI3K, was transcriptionally repressed by luteolin via induction of tumor suppressor mixed-lineage leukemia 3 (MLL3) expression. MLL3 increases the level of monomethylation of Histone 3 Lysine 4 on the enhancer and promoter region of Ras genes, thus causes repression of Ras expressions. Our finding implies that luteolin was a promising natural agent against tamoxifen resistance of breast cancer.

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