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Title: Phosphoproteome Analysis Reveals Estrogen-ER pathway as a modulator of mTOR activity via DEPTOR

Abstract

ER-positive breast tumors represent approximately 70% of all breast cancer cases. Although their treatment with endocrine therapies is effective in the adjuvant or recurrent settings, the development of resistance compromises their effectiveness. The binding of estrogen to ERa, a transcription factor, triggers the regulation of the target genes (genomic pathway). Additionally, a cytoplasmic fraction of estrogen-bound ERa activates oncogenic signaling pathways such as PI3K/AKT/mTOR (nongenomic pathway). The upregulation of the estrogenic and the PI3K/AKT/mTOR signaling pathways are frequently associated with a poor outcome. To better characterize the connection between these two pathways, we performed a phosphoproteome analysis of ER-positive MCF7 breast cancer cells treated with estrogen or estrogen and the mTORC1 inhibitor rapamycin. Many proteins were identified as estrogen-regulated mTORC1 targets and among them, DEPTOR was selected for further characterization. DEPTOR binds to mTOR and inhibits the kinase activity of both mTOR complexes mTORC1 and mTORC2, but mitogen-activated mTOR promotes phosphorylation-mediated DEPTOR degradation. Although estrogen enhances the phosphorylation of DEPTOR by mTORC1, DEPTOR levels increase in estrogen-stimulated cells. We demonstrated that DEPTOR accumulation is the result of estrogen-ERa-mediated transcriptional upregulation of DEPTOR expression. Consequently, the elevated levels of DEPTOR partially counterbalance the estrogen-induced activation of mTORC1 and mTORC2. These resultsmore » underscore the critical role of estrogen-ERa as a modulator of the PI3K/AKT/mTOR signaling pathway in ER-positive breast cancer cells. Additionally, these studies provide evidence supporting the use of dual PI3K/mTOR or dual mTORC1/2 inhibitors in combination with endocrine therapies as a first-line treatment option for the patients with ER-positive advanced breast cancer.« less

Authors:
 [1];  [2]; ORCiD logo [2]; ORCiD logo [2];  [2]; ORCiD logo [2]; ORCiD logo [2];  [3]
  1. New York Medical College
  2. BATTELLE (PACIFIC NW LAB)
  3. Albert Einstein Cancer Center
Publication Date:
Research Org.:
Pacific Northwest National Lab. (PNNL), Richland, WA (United States)
Sponsoring Org.:
USDOE
OSTI Identifier:
1599101
Report Number(s):
PNNL-SA-145628
DOE Contract Number:  
AC05-76RL01830
Resource Type:
Journal Article
Journal Name:
Molecular and Cellular Proteomics
Additional Journal Information:
Journal Volume: 18; Journal Issue: 8
Country of Publication:
United States
Language:
English

Citation Formats

Cuesta, Rafael, Gritsenko, Marina A., Petyuk, Vladislav A., Shukla, Anil K., Tsai, Chia-Feng, Liu, Tao, McDermott, Jason E., and Holz, Marina. Phosphoproteome Analysis Reveals Estrogen-ER pathway as a modulator of mTOR activity via DEPTOR. United States: N. p., 2019. Web. doi:10.1074/mcp.RA119.001506.
Cuesta, Rafael, Gritsenko, Marina A., Petyuk, Vladislav A., Shukla, Anil K., Tsai, Chia-Feng, Liu, Tao, McDermott, Jason E., & Holz, Marina. Phosphoproteome Analysis Reveals Estrogen-ER pathway as a modulator of mTOR activity via DEPTOR. United States. doi:10.1074/mcp.RA119.001506.
Cuesta, Rafael, Gritsenko, Marina A., Petyuk, Vladislav A., Shukla, Anil K., Tsai, Chia-Feng, Liu, Tao, McDermott, Jason E., and Holz, Marina. Thu . "Phosphoproteome Analysis Reveals Estrogen-ER pathway as a modulator of mTOR activity via DEPTOR". United States. doi:10.1074/mcp.RA119.001506.
@article{osti_1599101,
title = {Phosphoproteome Analysis Reveals Estrogen-ER pathway as a modulator of mTOR activity via DEPTOR},
author = {Cuesta, Rafael and Gritsenko, Marina A. and Petyuk, Vladislav A. and Shukla, Anil K. and Tsai, Chia-Feng and Liu, Tao and McDermott, Jason E. and Holz, Marina},
abstractNote = {ER-positive breast tumors represent approximately 70% of all breast cancer cases. Although their treatment with endocrine therapies is effective in the adjuvant or recurrent settings, the development of resistance compromises their effectiveness. The binding of estrogen to ERa, a transcription factor, triggers the regulation of the target genes (genomic pathway). Additionally, a cytoplasmic fraction of estrogen-bound ERa activates oncogenic signaling pathways such as PI3K/AKT/mTOR (nongenomic pathway). The upregulation of the estrogenic and the PI3K/AKT/mTOR signaling pathways are frequently associated with a poor outcome. To better characterize the connection between these two pathways, we performed a phosphoproteome analysis of ER-positive MCF7 breast cancer cells treated with estrogen or estrogen and the mTORC1 inhibitor rapamycin. Many proteins were identified as estrogen-regulated mTORC1 targets and among them, DEPTOR was selected for further characterization. DEPTOR binds to mTOR and inhibits the kinase activity of both mTOR complexes mTORC1 and mTORC2, but mitogen-activated mTOR promotes phosphorylation-mediated DEPTOR degradation. Although estrogen enhances the phosphorylation of DEPTOR by mTORC1, DEPTOR levels increase in estrogen-stimulated cells. We demonstrated that DEPTOR accumulation is the result of estrogen-ERa-mediated transcriptional upregulation of DEPTOR expression. Consequently, the elevated levels of DEPTOR partially counterbalance the estrogen-induced activation of mTORC1 and mTORC2. These results underscore the critical role of estrogen-ERa as a modulator of the PI3K/AKT/mTOR signaling pathway in ER-positive breast cancer cells. Additionally, these studies provide evidence supporting the use of dual PI3K/mTOR or dual mTORC1/2 inhibitors in combination with endocrine therapies as a first-line treatment option for the patients with ER-positive advanced breast cancer.},
doi = {10.1074/mcp.RA119.001506},
journal = {Molecular and Cellular Proteomics},
number = 8,
volume = 18,
place = {United States},
year = {2019},
month = {8}
}

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