MACROD2overexpression mediates estrogen independent growth and tamoxifen resistance in breast cancers

Abstract Background Tamoxifen resistance presents a huge clinical challenge for breast cancer patients. An understanding of the mechanisms of tamoxifen resistance can guide development of efficient therapies to prevent drug resistance. Methods We first tested whether peptidylarginine deiminase 2 (PAD2) may be involved in tamoxifen-resistance in breast cancer cells. The effect of depleting or inhibiting PAD2 in tamoxifen-resistant MCF-7 (MCF7/TamR) cells was evaluated both in vitro and in vivo. We then investigated the potential of Cl-amidine, a PAD inhibitor, to be used in combination with tamoxifen or docetaxel, and further explored the mechanism of the synergistic and effective drug regimen of PADs inhibitor and docetaxel on tamoxifen-resistant breast cancer cells. Results We report that PAD2 is dramatically upregulated in tamoxifen-resistant breast cancer. Depletion of PAD2 in MCF7/TamR cells facilitated the sensitivity of MCF7/TamR cells to tamoxifen. Moreover, miRNA-125b-5p negatively regulated PAD2 expression in MCF7/TamR cells, therefore overexpression of miR-125b-5p also increased the cell sensitivity to tamoxifen. Furthermore, inhibiting PAD2 with Cl-amidine not only partially restored the sensitivity of MCF7/TamR cells to tamoxifen, but also more efficiently enhanced the efficacy of docetaxel on MCF7/TamR cells with lower doses of Cl-amidine and docetaxel both in vivo and in vivo. We then showed that combination treatment with Cl-amidine and docetaxel enhanced p53 nuclear accumulation, which synergistically induced cell cycle arrest and apoptosis. Meanwhile, p53 activation in the combination treatment also accelerated autophagy processes by synergistically decreasing the activation of Akt/mTOR signaling, thus enhancing the inhibition of proliferation. Conclusion Our results suggest that PAD2 functions as an important new biomarker for tamoxifen-resistant breast cancers and that inhibiting PAD2 combined with docetaxel may offer a new approach to treatment of tamoxifen-resistant breast cancers.

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miR-489 confines uncontrolled estrogen signaling through a negative feedback mechanism and regulates tamoxifen resistance in breast cancer

10.21203/rs.3.rs-131460/v1 ◽

2020 ◽

Author(s):

Mithil Soni ◽

Ozge Saatci ◽

Yogin Patel ◽

Manikanda Raja Keerthi Raja ◽

Xinfeng Liu ◽

...

Keyword(s):

Breast Cancer ◽

Estrogen Receptor ◽

Cell Lines ◽

Tamoxifen Resistance ◽

Resistant Cell ◽

Estrogen Signaling ◽

Breast Cancers ◽

Tamoxifen Resistant ◽

Hormonal Therapies

Abstract Background Approximately 75% of diagnosed breast cancer tumors are Estrogen receptor (ER) positive tumors and are associated with better prognosis due to their response to hormonal therapies. However, around 40% of patients relapse after hormonal therapies. In the current study, we aimed to evaluate miR-489 as a novel molecular target to combat tamoxifen resistance.Methods Genomic analysis of gene expression profiles in primary breast cancers and tamoxifen resistant cell lines unveiled the potential role of miR-489 in regulation of estrogen signaling and development of tamoxifen resistance. We manipulated miR-489 expression in breast cancer cell lines by transient transfection of miR-489 mimic or establishment of knockout cell lines using the CRISPR/Cas9 system to study the reciprocal regulation of miR-489 and estrogen/ER signaling pathways. Cell proliferation, tumor sphere formation assay and flow cytometry analysis were conducted to investigate the role of miR-489 on estrogen-induced cell proliferation, cancer stem cells expansion and development of tamoxifen resistance.Results miR-489 expression was significantly downregulated in tamoxifen-resistant cell lines. Low levels of miR-489 were associated with poor clinical outcomes in patients with hormone treatment. In vitro analysis showed that loss of miR-489 expression promoted tamoxifen resistance while overexpression of miR-489 in tamoxifen-resistant cells restored tamoxifen sensitivity. Mechanistically, we found that miR-489 is an estrogen regulated miRNA that negatively regulated estrogen receptor signaling by using at least the following two mechanisms: i) modulation of ER phosphorylation status by inhibiting MAPK and AKT kinase activities; ii) regulation of nucleus to cytosol translocation of estrogen receptor α (ERα) by decreasing p38 expression and consequently ER phosphorylation. In addition, miR-489 could break the positive feed-forward loop between estrogen-ERα axis and p38 MAPK in breast cancer cells which was necessary for its function as transcription factor.Conclusion Our study unveiled the underlying molecular mechanism by which miR-489 regulates estrogen signaling pathway through a negative feedback loop and uncovered its role in the development of and overcoming tamoxifen resistance in breast cancers.

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Immunohistochemical assessment of PTEN expression and itsassociation with tamoxifen resistance in ER positive breast cancers

Galle Medical Journal ◽

10.4038/gmj.v26i3.8101 ◽

2021 ◽

Vol 26 (3) ◽

pp. 105

Author(s):

T. W. Wijesiri ◽

H. H. Peiris ◽

L. K. B. Mudduwa

Keyword(s):

Tamoxifen Resistance ◽

Pten Expression ◽

Breast Cancers ◽

Er Positive ◽

Immunohistochemical Assessment

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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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Embryonic transcription factor SOX9 drives breast cancer endocrine resistance

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1620993114 ◽

2017 ◽

Vol 114 (22) ◽

pp. E4482-E4491 ◽

Cited By ~ 47

Author(s):

Rinath Jeselsohn ◽

MacIntosh Cornwell ◽

Matthew Pun ◽

Gilles Buchwalter ◽

Mai Nguyen ◽

...

Keyword(s):

Breast Cancer ◽

Breast Cancer Cells ◽

Endocrine Resistance ◽

Tamoxifen Resistance ◽

Clinical Samples ◽

Breast Cancers ◽

Primary Target ◽

Metastatic Phenotype ◽

Clinical Observations ◽

Tamoxifen Resistant

The estrogen receptor (ER) drives the growth of most luminal breast cancers and is the primary target of endocrine therapy. Although ER blockade with drugs such as tamoxifen is very effective, a major clinical limitation is the development of endocrine resistance especially in the setting of metastatic disease. Preclinical and clinical observations suggest that even following the development of endocrine resistance, ER signaling continues to exert a pivotal role in tumor progression in the majority of cases. Through the analysis of the ER cistrome in tamoxifen-resistant breast cancer cells, we have uncovered a role for an RUNX2–ER complex that stimulates the transcription of a set of genes, including most notably the stem cell factor SOX9, that promote proliferation and a metastatic phenotype. We show that up-regulation of SOX9 is sufficient to cause relative endocrine resistance. The gain of SOX9 as an ER-regulated gene associated with tamoxifen resistance was validated in a unique set of clinical samples supporting the need for the development of improved ER antagonists.

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G-Protein Coupled Estrogen Receptor in Breast Cancer

International Journal of Molecular Sciences ◽

10.3390/ijms20020306 ◽

2019 ◽

Vol 20 (2) ◽

pp. 306 ◽

Cited By ~ 18

Author(s):

Li-Han Hsu ◽

Nei-Min Chu ◽

Yung-Feng Lin ◽

Shu-Huei Kao

Keyword(s):

Breast Cancer ◽

Estrogen Receptor ◽

G Protein ◽

Growth Factor Receptor ◽

Tamoxifen Resistance ◽

Breast Cancers ◽

Epidermal Growth ◽

Cancer Tissues ◽

G Protein Coupled ◽

Positive Breast Cancer

The G-protein coupled estrogen receptor (GPER), an alternate estrogen receptor (ER) with a structure distinct from the two canonical ERs, being ERα, and ERβ, is expressed in 50% to 60% of breast cancer tissues and has been presumed to be associated with the development of tamoxifen resistance in ERα positive breast cancer. On the other hand, triple-negative breast cancer (TNBC) constitutes 15% to 20% of breast cancers and frequently displays a more aggressive behavior. GPER is prevalent and involved in TNBC and can be a therapeutic target. However, contradictory results exist regarding the function of GPER in breast cancer, proliferative or pro-apoptotic. A better understanding of the GPER, its role in breast cancer, and the interactions with the ER and epidermal growth factor receptor will be beneficial for the disease management and prevention in the future.

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Signal therapy of breast cancers by the HDAC inhibitor FK228 that blocks the activation of PAK1 and abrogates the tamoxifen-resistance

Cancer Biology & Therapy ◽

10.4161/cbt.4.9.1911 ◽

2005 ◽

Vol 4 (9) ◽

pp. 956-960 ◽

Cited By ~ 51

Author(s):

Yumiko Hirokawa ◽

Melissa Arnold ◽

Hidenori Nakajima ◽

John Zalcberg ◽

Hiroshi Maruta

Keyword(s):

Hdac Inhibitor ◽

Tamoxifen Resistance ◽

Breast Cancers

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AFF3 upregulation mediates tamoxifen resistance in breast cancers

Journal of Experimental & Clinical Cancer Research ◽

10.1186/s13046-018-0928-7 ◽

2018 ◽

Vol 37 (1) ◽

Cited By ~ 3

Author(s):

Yawei Shi ◽

Yang Zhao ◽

Yunjian Zhang ◽

NiJiati AiErken ◽

Nan Shao ◽

...

Keyword(s):

Tamoxifen Resistance ◽

Breast Cancers

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TARBP2-Enhanced Resistance during Tamoxifen Treatment in Breast Cancer

Cancers ◽

10.3390/cancers11020210 ◽

2019 ◽

Vol 11 (2) ◽

pp. 210 ◽

Cited By ~ 1

Author(s):

Ming-Yang Wang ◽

Hsin-Yi Huang ◽

Yao-Lung Kuo ◽

Chiao Lo ◽

Hung-Yu Sun ◽

...

Keyword(s):

Breast Cancer ◽

Hormone Therapy ◽

Cancer Cells ◽

Breast Cancer Cells ◽

Cancer Metastasis ◽

Rna Binding ◽

Tamoxifen Resistance ◽

Breast Cancer Metastasis ◽

Tamoxifen Treatment ◽

Breast Cancers

Tamoxifen is the most widely used hormone therapy in estrogen receptor-positive (ER+) breast cancer, which accounts for approximately 70% of all breast cancers. Although patients who receive tamoxifen therapy benefit with respect to an improved overall prognosis, resistance and cancer recurrence still occur and remain important clinical challenges. A recent study identified TAR (HIV-1) RNA binding protein 2 (TARBP2) as an oncogene that promotes breast cancer metastasis. In this study, we showed that TARBP2 is overexpressed in hormone therapy-resistant cells and breast cancer tissues, where it enhances tamoxifen resistance. Tamoxifen-induced TARBP2 expression results in the desensitization of ER+ breast cancer cells. Mechanistically, tamoxifen post-transcriptionally stabilizes TARBP2 protein through the downregulation of Merlin, a TARBP2-interacting protein known to enhance its proteasomal degradation. Tamoxifen-induced TARBP2 further stabilizes SOX2 protein to enhance desensitization of breast cancer cells to tamoxifen, while similar to TARBP2, its induction in cancer cells was also observed in metastatic tumor cells. Our results indicate that the TARBP2-SOX2 pathway is upregulated by tamoxifen-mediated Merlin downregulation, which subsequently induces tamoxifen resistance in ER+ breast cancer.

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