scholarly journals Loss of HAS2 Confers Acquired Antiestrogen Resistance By Upregulating Ezrin Expression In ER-Positive Breast Cancer

2022 ◽  
Author(s):  
Xiaodan Sun ◽  
Fen Tang ◽  
Yiwen Liu ◽  
Yiqing He ◽  
Yan Du ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Mapk Signaling ◽  
Erk Signaling ◽  
Signaling Cascade ◽  
Ezrin Expression ◽  
Er Positive ◽  
Positive Breast Cancer

Abstract Background: Resistance to endocrine therapy is a major challenge for estrogen receptor-positive (ER+) breast cancer patients, but the underlying mechanisms remain unclear. Methods: Loss of hyaluronan synthase 2 (Has2) in adaptive resistant cells to tamoxifen and fulvestrant was observed by immunblotting assay. CRISPR/Cas9 technology was used to knock out Has2 in MCF7 cells to verify the effect of Has2 on the expression of ER and Ezrin and Akt and MAPK/ERK signaling routes. We utilized an Ezrin small-interfering RNA and Ezrin inhibitor to inhibit Ezrin expression for evaluating Has2 and ERα expression and the Akt/MAPK signaling cascade upon tamoxifen or fulvestrant treatment.Results: In this work, we showed that a Has2-loss state was acquired from adaptive resistance to tamoxifen and fulvestrant in luminal BrCas. Notably, the adapted loss of Has2 induced acquired resistance to antiestrogens in estrogen receptor (ER)-positive breast cancer cells through up-regulating the expression of Ezrin. Furthermore, we found that the loss of Has2 promoted while the consequent increase of Ezrin inhibited ERα expression/activity through the Akt and MAPK/ERK signaling routes, indicating an opposite effect on ERα expression during the development of antiestrogens-resistance. Inhibition of Ezrin reversed Has2 and ERα expression and the Akt/MAPK signaling cascade upon tamoxifen or fulvestrant, suggesting a Has2-Ezrin-ER negative-feedback loop in governing cellular sensitivity to tamoxifen or fulvestrant in luminal-like breast cancer cells. Finally, Knockdown or inhibition of Ezrin restored sensitivity to antiestrogens, implying that Ezrin could be a potential therapeutic target to tackle endocrine resistance. Conclusions: Taken together, our findings provide a direct relationship between ERα and Has2 implicated in resistance to endocrine therapy and a new insight into how ERα-signaling is regulated upon antiestrogens treatment, suggesting a novel therapeutic target for ER-positive breast cancer.

scholarly journals Loss of HAS2 Confers Acquired Antiestrogen Resistance by Upregulating Ezrin Expression in ER-Positive Breast Cancer

2021 ◽  
Author(s):  
Xiaodan Sun ◽  
Fen Tang ◽  
Yiwen Liu ◽  
Yiqing He ◽  
Yan Du ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Mapk Signaling ◽  
Erk Signaling ◽  
Signaling Cascade ◽  
Ezrin Expression ◽  
Er Positive ◽  
Positive Breast Cancer

Abstract Background: Resistance to endocrine therapy is a major challenge for estrogen receptor-positive (ER+) breast cancer patients, but the underlying mechanisms remain unclear. Methods: Loss of hyaluronan synthase 2 (Has2) in adaptive resistant cells to tamoxifen and fulvestrant was observed by immunblotting assay. CRISPR/Cas9 technology was used to knock out Has2 in MCF7 cells to verify the effect of Has2 on the expression of ER and Ezrin and Akt and MAPK/ERK signaling routes. We utilized an Ezrin small-interfering RNA and Ezrin inhibitor to inhibit Ezrin expression for evaluating Has2 and ERα expression and the Akt/MAPK signaling cascade upon tamoxifen or fulvestrant treatment.Results: In this work, we showed that a Has2-loss state was acquired from adaptive resistance to tamoxifen and fulvestrant in luminal BrCas. Notably, the adapted loss of Has2 induced acquired resistance to antiestrogens in estrogen receptor (ER)-positive breast cancer cells through up-regulating the expression of Ezrin. Furthermore, we found that the loss of Has2 promoted while the consequent increase of Ezrin inhibited ERα expression/activity through the Akt and MAPK/ERK signaling routes, indicating an opposite effect on ERα expression during the development of antiestrogens-resistance. Inhibition of Ezrin reversed Has2 and ERα expression and the Akt/MAPK signaling cascade upon tamoxifen or fulvestrant, suggesting a Has2-Ezrin-ER negative-feedback loop in governing cellular sensitivity to tamoxifen or fulvestrant in luminal-like breast cancer cells. Finally, Knockdown or inhibition of Ezrin restored sensitivity to antiestrogens, implying that Ezrin could be a potential therapeutic target to tackle endocrine resistance. Conclusions: Taken together, our findings provide a direct relationship between ERα and Has2 implicated in resistance to endocrine therapy and a new insight into how ERα-signaling is regulated upon antiestrogens treatment, suggesting a novel therapeutic target for ER-positive breast cancer.

scholarly journals Heat Shock Factor 1 (HSF1) cooperates with estrogen receptor α (ERα) in the regulation of estrogen action in breast cancer cells

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Natalia Vydra ◽  
Patryk Janus ◽  
Paweł Kuś ◽  
Tomasz Stokowy ◽  
Katarzyna Mrowiec ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Heat Shock ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Estrogen Receptor Α ◽  
Heat Shock Factor ◽  
Heat Shock Factor 1 ◽  
Er Positive ◽  
Positive Breast Cancer

Heat shock factor 1 (HSF1), a key regulator of transcriptional responses to proteotoxic stress, was linked to estrogen (E2) signaling through estrogen receptor α (ERα). We found that an HSF1 deficiency may decrease ERα level, attenuate the mitogenic action of E2, counteract E2-stimulated cell scattering, and reduce adhesion to collagens and cell motility in ER-positive breast cancer cells. The stimulatory effect of E2 on the transcriptome is largely weaker in HSF1-deficient cells, in part due to the higher basal expression of E2-dependent genes, which correlates with the enhanced binding of unliganded ERα to chromatin in such cells. HSF1 and ERα can cooperate directly in E2-stimulated regulation of transcription, and HSF1 potentiates the action of ERα through a mechanism involving chromatin reorganization. Furthermore, HSF1 deficiency may increase the sensitivity to hormonal therapy (4-hydroxytamoxifen) or CDK4/6 inhibitors (palbociclib). Analyses of data from the TCGA database indicate that HSF1 increases the transcriptome disparity in ER-positive breast cancer and can enhance the genomic action of ERα. Moreover, only in ER-positive cancers, an elevated HSF1 level is associated with metastatic disease.

scholarly journals The mechanisms involved in the resistance of estrogen receptor-positive breast cancer cells to palbociclib are multiple and change over time

2021 ◽  
Author(s):  
Mayu Ono ◽  
Takaaki Oba ◽  
Tomohiro Shibata ◽  
Ken-ichi Ito
Keyword(s):  
Breast Cancer ◽  
Cell Cycle ◽  
Estrogen Receptor ◽  
Cancer Cells ◽  
Copy Number ◽  
Breast Cancer Cells ◽  
Copy Number Alterations ◽  
Altered Expression ◽  
Er Positive ◽  
Positive Breast Cancer

Abstract Purpose Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors are widely used for the treatment of advanced estrogen receptor (ER)-positive breast cancer. To develop a treatment strategy for cancers resistant to CDK4/6 inhibitors, here, we established palbociclib-resistant sublines and analyzed their resistance mechanisms. Methods Palbociclib-resistant sublines were established from T47D and MCF7 cells. Sensitivity to other drugs was assessed via the WST assay. Altered expression/phosphorylation of proteins related to signal transduction and cell cycle regulation was examined using western blotting. Copy number alterations and mutations in the retinoblastoma (RB1) gene were also analyzed. Results Although an increase in CDK6 and decrease in retinoblastoma protein (Rb) expression/phosphorylation were commonly observed in the resistant sublines, changes in other cell cycle-related proteins were heterogeneous. Upon extended exposure to palbociclib, the expression/phosphorylation of these proteins became altered, and the long-term removal of palbociclib did not restore the Rb expression/phosphorylation patterns. Consistently a copy number decrease, as well as RB1 mutations were detected. Moreover, although the resistant sublines exhibited cross-resistance to abemaciclib, their response to dinaciclib was the same as that of wild-type cells. Of note, the cell line exhibiting increased mTOR phosphorylation also showed a higher sensitivity to everolimus. However, the sensitivity to chemotherapeutic agents was unchanged in palbociclib-resistant sublines. Conclusion ER-positive breast cancer cells use multiple molecular mechanisms to survive in the presence of palbociclib, suggesting that targeting activated proteins may be an effective strategy to overcome resistance. Additionally, palbociclib monotherapy induces mutations and copy number alterations in the RB1 gene.

scholarly journals Estrogen-induced interaction between KLF5 and estrogen receptor (ER) suppresses the function of ER in ER-positive breast cancer cells

2010 ◽  
Vol 126 (1) ◽  
pp. 81-89 ◽  
Author(s):  
Peng Guo ◽  
Xue-Yuan Dong ◽  
Ke-Wen Zhao ◽  
Xiaodong Sun ◽  
Qunna Li ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Er Positive ◽  
Positive Breast Cancer

scholarly journals ATBF1 Inhibits Estrogen Receptor (ER) Function by Selectively Competing with AIB1 for Binding to the ER in ER-positive Breast Cancer Cells

2010 ◽  
Vol 285 (43) ◽  
pp. 32801-32809 ◽  
Author(s):  
Xue-Yuan Dong ◽  
Xiaodong Sun ◽  
Peng Guo ◽  
Qunna Li ◽  
Masakiyo Sasahara ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Er Positive ◽  
Positive Breast Cancer

scholarly journals Akt2 Inhibition Enables the Forkhead Transcription Factor FoxO3a To Have a Repressive Role in Estrogen Receptor α Transcriptional Activity in Breast Cancer Cells

2009 ◽  
Vol 30 (3) ◽  
pp. 857-870 ◽  
Author(s):  
Catia Morelli ◽  
Marilena Lanzino ◽  
Cecilia Garofalo ◽  
Pamela Maris ◽  
Elvira Brunelli ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Transcription Factor ◽  
Growth Factor ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Transcriptional Activity ◽  
Forkhead Transcription Factor ◽  
Er Positive ◽  
Positive Breast Cancer

ABSTRACT Estrogen receptor alpha (ER) and the insulin-like growth factor I receptor (IGF-IR) pathways are engaged in a functional cross talk in breast cancer, promoting tumor progression and increased resistance to anticancer treatments and radiotherapy. Here, we introduce new mechanisms through which proteins of the IGF-I/IGF-IR signaling pathway may regulate ER function in the absence of ligand. Our results indicate that in ER-positive breast cancer cells, Akt2 modulates ER transcriptional activity at multiple levels, including (i) the regulation of ER expression and its nuclear retention and (ii) the activation of one of its downstream targets, the Forkhead transcription factor FoxO3a. FoxO3a colocalizes and coprecipitates with ER in the nucleus, where it binds to Forkhead-responsive sequences on the ER target pS2/TFF-1 promoter; in addition, FoxO3a silencing leads to an increase of ER transcriptional activity, suggesting a repressive role of the Forkhead transcription factor in ER function. Moreover, 17β-estradiol upregulates FoxO3a levels, which could represent the basis for an ER-mediated homeostatic mechanism. These findings provide further evidence of the importance of mediators of the growth factor signaling in ER regulation, introducing the Akt2/FoxO3a axis as a pursuable target in therapy for ER-positive breast cancer.

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