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Crosstalk between mTOR and Estrogen Signaling
Author(s) -
Holz Marina
Publication year - 2020
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2020.34.s1.00221
Subject(s) - pi3k/akt/mtor pathway , mtorc1 , estrogen , protein kinase b , downregulation and upregulation , crosstalk , signal transduction , cancer research , microbiology and biotechnology , mtorc2 , phosphorylation , chemistry , estrogen receptor , biology , endocrinology , biochemistry , breast cancer , cancer , gene , genetics , physics , optics
Binding of estrogen to ERα triggers the regulation of the target genes (genomic pathway). Additionally, a cytoplasmic fraction of estrogen‐bound ERα activates oncogenic signaling pathways such as PI3K/AKT/mTOR (nongenomic pathway). The upregulation of the estrogenic and the PI3K/AKT/mTOR signaling pathways is frequently associated with a poor outcome in breast cancer. To better characterize the connection between these two pathways, we performed a phosphoproteome analysis of estrogen and mTORC1 signaling. We identified two inhibitory proteins, DEPTOR end eIF3f, as estrogen‐regulated mTORC1 targets. DEPTOR binds to mTOR and inhibits its kinase activity. 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‐ERα‐mediated transcriptional upregulation of DEPTOR expression. Consequently, the elevated levels of DEPTOR partially counterbalance the estrogen‐induced activation of mTORC1/2. We also found that the expression of the translation pre‐initiation inhibitory protein eIF3f is tightly controlled by ERα at the transcriptional and translational levels. Specifically, estrogen‐bound ERα represses transcription of the EIF3F gene, while promoting eIF3f mRNA translation. To regulate translation, estrogen activates the mTORC1 pathway. These results underscore the critical role of estrogen‐ERα as a modulator of the PI3K/AKT/mTOR signaling pathway in ER‐positive breast cancer cells. Support or Funding Information NIH R35GM128675