Glucocorticoid Receptor Signaling Activates TEAD4 to Promote Breast Cancer Progression
©2019 American Association for Cancer Research..
The Hippo pathway plays a critical role in cell growth and tumorigenesis. The activity of TEA domain transcription factor 4 (TEAD4) determines the output of Hippo signaling; however, the regulation and function of TEAD4 has not been explored extensively. Here, we identified glucocorticoids (GC) as novel activators of TEAD4. GC treatment facilitated glucocorticoid receptor (GR)-dependent nuclear accumulation and transcriptional activation of TEAD4. TEAD4 positively correlated with GR expression in human breast cancer, and high expression of TEAD4 predicted poor survival of patients with breast cancer. Mechanistically, GC activation promoted GR interaction with TEAD4, forming a complex that was recruited to the TEAD4 promoter to boost its own expression. Functionally, the activation of TEAD4 by GC promoted breast cancer stem cells maintenance, cell survival, metastasis, and chemoresistance both in vitro and in vivo. Pharmacologic inhibition of TEAD4 inhibited GC-induced breast cancer chemoresistance. In conclusion, our study reveals a novel regulation and functional role of TEAD4 in breast cancer and proposes a potential new strategy for breast cancer therapy. SIGNIFICANCE: This study provides new insight into the role of glucocorticoid signaling in breast cancer, with potential for clinical translation.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2019 |
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| Erschienen: |
2019 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:79 |
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| Enthalten in: |
Cancer research - 79(2019), 17 vom: 01. Sept., Seite 4399-4411 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
He, Lingli [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 15.06.2020 Date Revised 04.12.2021 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1158/0008-5472.CAN-19-0012 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM299023907 |
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| 100 | 1 | |a He, Lingli |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Glucocorticoid Receptor Signaling Activates TEAD4 to Promote Breast Cancer Progression |
| 264 | 1 | |c 2019 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
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| 500 | |a Date Completed 15.06.2020 | ||
| 500 | |a Date Revised 04.12.2021 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a ©2019 American Association for Cancer Research. | ||
| 520 | |a The Hippo pathway plays a critical role in cell growth and tumorigenesis. The activity of TEA domain transcription factor 4 (TEAD4) determines the output of Hippo signaling; however, the regulation and function of TEAD4 has not been explored extensively. Here, we identified glucocorticoids (GC) as novel activators of TEAD4. GC treatment facilitated glucocorticoid receptor (GR)-dependent nuclear accumulation and transcriptional activation of TEAD4. TEAD4 positively correlated with GR expression in human breast cancer, and high expression of TEAD4 predicted poor survival of patients with breast cancer. Mechanistically, GC activation promoted GR interaction with TEAD4, forming a complex that was recruited to the TEAD4 promoter to boost its own expression. Functionally, the activation of TEAD4 by GC promoted breast cancer stem cells maintenance, cell survival, metastasis, and chemoresistance both in vitro and in vivo. Pharmacologic inhibition of TEAD4 inhibited GC-induced breast cancer chemoresistance. In conclusion, our study reveals a novel regulation and functional role of TEAD4 in breast cancer and proposes a potential new strategy for breast cancer therapy. SIGNIFICANCE: This study provides new insight into the role of glucocorticoid signaling in breast cancer, with potential for clinical translation | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 7 | |a Adaptor Proteins, Signal Transducing |2 NLM | |
| 650 | 7 | |a DNA-Binding Proteins |2 NLM | |
| 650 | 7 | |a Glucocorticoids |2 NLM | |
| 650 | 7 | |a Muscle Proteins |2 NLM | |
| 650 | 7 | |a Receptors, Glucocorticoid |2 NLM | |
| 650 | 7 | |a TEA Domain Transcription Factors |2 NLM | |
| 650 | 7 | |a TEAD4 protein, human |2 NLM | |
| 650 | 7 | |a Trans-Activators |2 NLM | |
| 650 | 7 | |a Transcription Factors |2 NLM | |
| 650 | 7 | |a Transcriptional Coactivator with PDZ-Binding Motif Proteins |2 NLM | |
| 650 | 7 | |a WWTR1 protein, human |2 NLM | |
| 650 | 7 | |a YAP-Signaling Proteins |2 NLM | |
| 650 | 7 | |a YAP1 protein, human |2 NLM | |
| 650 | 7 | |a Niflumic Acid |2 NLM | |
| 650 | 7 | |a 4U5MP5IUD8 |2 NLM | |
| 650 | 7 | |a Dexamethasone |2 NLM | |
| 650 | 7 | |a 7S5I7G3JQL |2 NLM | |
| 700 | 1 | |a Yuan, Liang |e verfasserin |4 aut | |
| 700 | 1 | |a Sun, Yang |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Pingyang |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Hailin |e verfasserin |4 aut | |
| 700 | 1 | |a Feng, Xue |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Zuoyun |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Wenxiang |e verfasserin |4 aut | |
| 700 | 1 | |a Yang, Chuanyu |e verfasserin |4 aut | |
| 700 | 1 | |a Zeng, Yi Arial |e verfasserin |4 aut | |
| 700 | 1 | |a Zhao, Yun |e verfasserin |4 aut | |
| 700 | 1 | |a Chen, Ceshi |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Lei |e verfasserin |4 aut | |
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