scholarly journals Mps1 contributes to tamoxifen resistance in Breast Cancer through phosphorylation of ERα

2021 ◽  
Author(s):  
Xuemiao Zhang ◽  
Qi Gao ◽  
Yulong Zong ◽  
Xueping Ma ◽  
Cuijuan Duan ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Transcriptional Activity ◽  
Tamoxifen Resistance ◽  
Tamoxifen Treatment ◽  
Great Promise ◽  
Dependent Manner ◽  
Mitotic Kinase ◽  
Monopolar Spindle

Abstract Overexpression of mitotic kinase monopolar spindle 1 (Mps1) has been identified in many tumor types and targeting Mps1 for tumor therapy has been shown great promise in multiple preclinical cancer models. However, the role of Mps1 in tamoxifen resistance in breast cancer has never been reported. Here in this study, we report that Mps1 determined the sensitivity of breast cancer cells to tamoxifen treatment. Mps1 overexpression rendered breast cancer cells more resistant to tamoxifen, while Mps1 inhibitor or siMps1 oligos could overcome tamoxifen resistance. Mechanistically, Mps1 interacted with ERα and stimulated its transcriptional activity in kinase activity-dependent manner. Mps1 was responsible for ERα phosphorylation at S559 and T224 sites. Importantly, Mps1 failed to enhance the transcriptional activity of ERα in the presence of ERα S559A or T224A mutant. Collectively, our findings suggest that Mps1 contributes to tamoxifen resistance in breast cancer and is a potential therapeutic to overcome tamoxifen resistance in breast cancer.

scholarly journals Poly-ADP-Ribosylation of Estrogen Receptor-Alpha by PARP1 Mediates Antiestrogen Resistance in Human Breast Cancer Cells

Cancers ◽  
2019 ◽  
Vol 11 (1) ◽  
pp. 43 ◽  
Author(s):  
Nicholas Pulliam ◽  
Jessica Tang ◽  
Weini Wang ◽  
Fang Fang ◽  
Riddhi Sood ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Oxidative Stress ◽  
Estrogen Receptor ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Target Genes ◽  
Tamoxifen Resistance ◽  
Tamoxifen Treatment ◽  
Dependent Manner ◽  
Tamoxifen Resistant

Therapeutic targeting of estrogen receptor-α (ERα) by the anti-estrogen tamoxifen is standard of care for premenopausal breast cancer patients and remains a key component of treatment strategies for postmenopausal patients. While tamoxifen significantly increases overall survival, tamoxifen resistance remains a major limitation despite continued expression of ERα in resistant tumors. Previous reports have described increased oxidative stress in tamoxifen resistant versus sensitive breast cancer and a role for PARP1 in mediating oxidative damage repair. We hypothesized that PARP1 activity mediated tamoxifen resistance in ERα-positive breast cancer and that combining the antiestrogen tamoxifen with a PARP1 inhibitor (PARPi) would sensitize tamoxifen resistant cells to tamoxifen therapy. In tamoxifen-resistant vs. -sensitive breast cancer cells, oxidative stress and PARP1 overexpression were increased. Furthermore, differential PARylation of ERα was observed in tamoxifen-resistant versus -sensitive cells, and ERα PARylation was increased by tamoxifen treatment. Loss of ERα PARylation following treatment with a PARP inhibitor (talazoparib) augmented tamoxifen sensitivity and decreased localization of both ERα and PARP1 to ERα-target genes. Co-administration of talazoparib plus tamoxifen increased DNA damage accumulation and decreased cell survival in a dose-dependent manner. The ability of PARPi to overcome tamoxifen resistance was dependent on ERα, as lack of ERα-mediated estrogen signaling expression and showed no response to tamoxifen-PARPi treatment. These results correlate ERα PARylation with tamoxifen resistance and indicate a novel mechanism-based approach to overcome tamoxifen resistance in ER+ breast cancer.

scholarly journals MiR-873 regulates ERα transcriptional activity and tamoxifen resistance via targeting CDK3 in breast cancer cells

Oncogene ◽  
2014 ◽  
Vol 34 (30) ◽  
pp. 3895-3907 ◽  
Author(s):  
J Cui ◽  
Y Yang ◽  
H Li ◽  
Y Leng ◽  
K Qian ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Transcriptional Activity ◽  
Tamoxifen Resistance

scholarly journals LAMP3 is involved in tamoxifen resistance in breast cancer cells through the modulation of autophagy

2014 ◽  
Vol 21 (1) ◽  
pp. 101-112 ◽  
Author(s):  
Anika Nagelkerke ◽  
Anieta M Sieuwerts ◽  
Johan Bussink ◽  
Fred C G J Sweep ◽  
Maxime P Look ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Mrna Expression ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Tamoxifen Resistance ◽  
Tamoxifen Treatment ◽  
Breast Cancer Patients ◽  
Mcf7 Cells ◽  
First Line ◽  
Tamoxifen Resistant

Lysosome-associated membrane protein 3 (LAMP3) is a member of the LAMP-family of proteins, which are involved in the process of autophagy. Autophagy is induced by tamoxifen in breast cancer cells and may contribute to tamoxifen resistance. In this study, the significance of LAMP3 for tamoxifen resistance in breast cancer was examined. The methods employed included use of clonogenic assays to assess the survival of MCF7 breast cancer cells with LAMP3 knockdown after tamoxifen treatment and of quantitative real-time PCR of LAMP3 to evaluate its predictive value for first-line tamoxifen treatment in patients with advanced breast cancer. Results show that tamoxifen treatment of MCF7 cells induced LAMP3 mRNA expression. LAMP3 knockdown in these cells increased tamoxifen sensitivity. Evaluation of expression of the autophagy markers, LC3B and p62, after LAMP3 knockdown showed increased expression levels, indicating that cells with LAMP3 knockdown have a suppressed ability to complete the autophagic process. In addition, knockdown of autophagy-associated genes resulted in sensitization to tamoxifen. Next, tamoxifen-resistant MCF7 cells were cultured. These cells had a sevenfold higher LAMP3 mRNA expression, showed elevated basal autophagy levels, and could be significantly resensitized to tamoxifen by LAMP3 knockdown. In patients treated with first-line tamoxifen for advanced disease (n=304), high LAMP3 mRNA expression was associated with shorter progression-free survival (P=0.003) and shorter post-relapse overall survival (P=0.040), also in multivariate analysis. Together, these results indicate that LAMP3 contributes to tamoxifen resistance in breast cancer. Tamoxifen-resistant cells are resensitized to tamoxifen by the knockdown of LAMP3. Therefore, LAMP3 may be clinically relevant to countering tamoxifen resistance in breast cancer patients.

scholarly journals Signal Transducer and Activator of Transcription 5b, c-Src, and Epidermal Growth Factor Receptor Signaling Play Integral Roles in Estrogen-Stimulated Proliferation of Estrogen Receptor-Positive Breast Cancer Cells

2008 ◽  
Vol 22 (8) ◽  
pp. 1781-1796 ◽  
Author(s):  
Emily M. Fox ◽  
Teresa M. Bernaciak ◽  
Jie Wen ◽  
Amanda M. Weaver ◽  
Margaret A. Shupnik ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cyclin D1 ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Transcriptional Activity ◽  
Growth Factor Receptor ◽  
Tamoxifen Resistance ◽  
Cancer Proliferation ◽  
Epidermal Growth ◽  
Mcf 7

Abstract 17β-Estradiol (E2) acts through the estrogen receptor α (ERα) to stimulate breast cancer proliferation. Here, we investigated the functional relationship between ERα and signal transducer and activator of transcription (STAT)5b activity in ER+ MCF-7 and T47D human breast cancer cells after specific knockdown of STAT5b. STAT5b small interfering RNA (siRNA) inhibited E2-induced bromodeoxyuridine (BrdU) incorporation in both cell lines, as well as the E2-induced increase in MCF-7 cell number, cyclin D1 and c-myc mRNA, and cyclin D1 protein expression, indicating that STAT5b is required for E2-stimulated breast cancer proliferation. E2 treatment stimulated STAT5b tyrosine phosphorylation at the activating tyrosine Y699, resulting in increased STAT5-mediated transcriptional activity, which was inhibited by a Y669F STAT5b mutant. E2-induced STAT5-mediated transcriptional activity was inhibited by overexpressing a kinase-defective epidermal growth factor receptor (EGFR), or the EGFR tyrosine kinase inhibitor tyrphostin AG1478, indicating a requirement for EGFR kinase activity. Both E2-induced STAT5b tyrosine phosphorylation and STAT5-mediated transcription were also inhibited by the ER antagonist ICI 182,780 and the c-Src inhibitor PP2, indicating additional requirements for the ER and c-Src kinase activity. EGFR and c-Src kinase activities were also required for E2-induced cyclin D1 and c-myc mRNA. Together, these studies demonstrate positive cross talk between ER, c-Src, EGFR, and STAT5b in ER+ breast cancer cells. Increased EGFR and c-Src signaling is associated with tamoxifen resistance in ER+ breast cancer cells. Here we show that constitutively active STAT5b not only increased basal DNA synthesis, but also conferred tamoxifen resistance. Because STAT5b plays an integral role in E2-stimulated proliferation and tamoxifen resistance, it may be an effective therapeutic target in ER+ breast tumors.

scholarly journals Erratum: MiR-873 regulates ERα transcriptional activity and tamoxifen resistance via targeting CDK3 in breast cancer cells

Oncogene ◽  
2015 ◽  
Vol 34 (30) ◽  
pp. 4018-4018 ◽  
Author(s):  
J Cui ◽  
Y Yang ◽  
H Li ◽  
Y Leng ◽  
K Qian ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Transcriptional Activity ◽  
Tamoxifen Resistance

Increasing tripartite cooperation of ER-alpha, c-Src, and IGF-1R plays an important role in tamoxifen resistance

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 11037-11037
Author(s):  
Y. Shu ◽  
Y. Yin ◽  
R. Guo ◽  
Y. Gu ◽  
L. Liu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Estrogen Receptor Alpha ◽  
Acquired Resistance ◽  
Tamoxifen Resistance ◽  
Inhibitory Effect ◽  
Mapk Signaling ◽  
Tamoxifen Treatment ◽  
Therapeutic Problem

11037 Background: Acquired resistance to tamoxifen is a serious therapeutic problem that limits its clinical benefit. The precise mechanisms for acquired tamoxifen resistance, however, are still not fully understood. Our prior studies suggest that enhancement interaction between growth factors and ERa was associated with development of tamoxifen resistance. Cross-talk between growth factor receptors and estrogen receptor alpha (ERa) makes this problem more complicated. We hypothesized that some other proteins may be involved in this association between two kinds receptors in the development of TAM resistance. Methods: To test our hypothesis, MCF-7 breast cancer cells were continuously treated with TAM (10–7 M) until the cells resist to tamoxifen treatment, which were named as tamoxifen resistant cells (TAM-R). Results: TAM-R cells were more sensitive to E2 and IGF-1 stimulation to express higher level phospho-MAPK than that of control cells. Inhibitory effect of AG1024 on TAM-R cells was about as 2 folds as many as that of control cells. MAPK inhibitor caused dramatic inhibition of growth of TAM-R cells. It was interestingly found that ERa translocated from nucleus to cytosol and an increased amount of ERa was co-immunoprecipitated with IGF-1R from TAM-R cells even though there was no change in the levels of these receptors compared to the control cells. c-Src was an important adapter protein between these two receptors, which increasingly combined with both IGF-1R and ERa in TAM-R cells. Pure antiestrogen ICI, AG1024/IGF-1R SiRNA, and Src family inhibitor PP2 could inhibit the interaction between IGF-1R and ERa. However, only PP2 could completely inhibit ERa translocate from nucleus to cytosol and cytoplasm membrane. Conclusions: Our results suggested that IGF-1R/MAPK signaling pathway was very important for TAM-R cells to develop resistance. c- Src was an critical elements to form a ternary complex with IGF-1R and ERa. This may be one mechanism responsible for tamoxifen resistance in breast cancer cells. No significant financial relationships to disclose.

scholarly journals TARBP2-Enhanced Resistance during Tamoxifen Treatment in Breast Cancer

Cancers ◽  
2019 ◽  
Vol 11 (2) ◽  
pp. 210 ◽  
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.

scholarly journals Cannabidiolic Acid-Mediated Interference with AP-1 Transcriptional Activity in MDA-MB-231 Breast Cancer Cells

2017 ◽  
Vol 12 (5) ◽  
pp. 1934578X1701200 ◽  
Author(s):  
Masayo Suzuki ◽  
Shuso Takeda ◽  
Hiroyuki Okazaki ◽  
Kazuhito Watanabe ◽  
Masufumi Takiguchi ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Transcriptional Activity ◽  
Fiber Type ◽  
Limiting Factor ◽  
Dependent Manner ◽  
Activator Protein 1 ◽  
Cannabidiolic Acid ◽  
Cox 2

We reported that cannabidiolic acid (CBDA), a non-psychotropic constituent of fiber-type cannabis plants, down-regulates the mRNA expression of cyclooxygenase-2 (COX-2) in highly aggressive MDA-MB-231 human breast cancer cells. However, the molecular mechanism(s) underlying the CBDA suppression of COX-2 have not yet been elucidated in detail. In MDA-MB-231 cells, COX-2 expression is known to be tightly regulated by the transcriptional activity of activator protein-1 (AP-1), which is composed of a heterodimer of c-Fos and c-Jun. AP-1-mediated transcriptional activity was inhibited by CBDA in a dose-dependent manner. The expression of c-fos was maintained at markedly lower levels (0.035) than basal c-jun expression levels (1.0), implicating c-fos as a limiting factor in the regulation of COX-2. Analyses indicated that CBDA abrogated the expression of c-fos mRNA without affecting c-jun. Collectively, these results suggest that CBDA abolishes the expression of COX-2 by interfering with AP-1 activity in MDA-MB-231 cells.

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