scholarly journals Estrogen receptor alpha controls gene expression via translational offsetting

2018 ◽  
Author(s):  
Julie Lorent ◽  
Richard J. Rebello ◽  
Vincent van Hoef ◽  
Mitchell G. Lawrence ◽  
Krzysztof J. Szkop ◽  
...  
Keyword(s):  
Estrogen Receptor ◽  
Estrogen Receptor Alpha ◽  
Mrna Translation ◽  
Translational Efficiency ◽  
Cancer Cell Proliferation ◽  
Altered Expression ◽  
Receptor Alpha ◽  
Protein Levels ◽  
Transcriptional Output ◽  
The Impact

AbstractEstrogen receptor alpha (ERα) activity is associated with increased cancer cell proliferation. Studies aiming to understand the impact of ERα on cancer-associated phenotypes have largely been limited to its transcriptional activity. Herein, we demonstrate that ERα coordinates its transcriptional output with selective modulation of mRNA translation. Importantly, translational perturbations caused by depletion of ERα largely manifest as “translational offsetting” of the transcriptome, whereby amounts of translated mRNA and protein levels are maintained constant despite changes in mRNA abundance. Transcripts whose levels, but not polysome-association, are reduced following ERα depletion lack features which limit translational efficiency including structured 5’UTRs and miRNA target sites. In contrast, mRNAs induced upon ERα depletion whose polysome-association remains unaltered are enriched in codons requiring U34-modified tRNAs for efficient decoding. Consistently, ERα regulates levels of U34-modification enzymes, whereas altered expression of U34-modification enzymes disrupts ERα dependent translational offsetting. Altogether, we unravel a hitherto unprecedented mechanism of ERα-dependent orchestration of transcriptional and translational programs, and highlight that translational offsetting may be a pervasive mechanism of proteome maintenance in hormone-dependent cancers.

scholarly journals Positive Regulation of Estrogen Receptor Alpha in Breast Tumorigenesis

Cells ◽  
2021 ◽  
Vol 10 (11) ◽  
pp. 2966
Author(s):  
Lucas Porras ◽  
Houssam Ismail ◽  
Sylvie Mader
Keyword(s):  
Estrogen Receptor ◽  
Estrogen Receptor Alpha ◽  
Uterine Cancer ◽  
Breast Tumors ◽  
Regulatory Elements ◽  
Genetic Alterations ◽  
Receptor Alpha ◽  
Esr1 Gene ◽  
The Impact ◽  
Esr1 Expression

Estrogen receptor alpha (ERα, NR3A1) contributes through its expression in different tissues to a spectrum of physiological processes, including reproductive system development and physiology, bone mass maintenance, as well as cardiovascular and central nervous system functions. It is also one of the main drivers of tumorigenesis in breast and uterine cancer and can be targeted by several types of hormonal therapies. ERα is expressed in a subset of luminal cells corresponding to less than 10% of normal mammary epithelial cells and in over 70% of breast tumors (ER+ tumors), but the basis for its selective expression in normal or cancer tissues remains incompletely understood. The mapping of alternative promoters and regulatory elements has delineated the complex genomic structure of the ESR1 gene and shed light on the mechanistic basis for the tissue-specific regulation of ESR1 expression. However, much remains to be uncovered to better understand how ESR1 expression is regulated in breast cancer. This review recapitulates the current body of knowledge on the structure of the ESR1 gene and the complex mechanisms controlling its expression in breast tumors. In particular, we discuss the impact of genetic alterations, chromatin modifications, and enhanced expression of other luminal transcription regulators on ESR1 expression in tumor cells.

scholarly journals Aptamer-Assisted Detection of the Altered Expression of Estrogen Receptor Alpha in Human Breast Cancer

PLoS ONE ◽  
2016 ◽  
Vol 11 (4) ◽  
pp. e0153001 ◽  
Author(s):  
Rajesh Ahirwar ◽  
Shamsudheen Karuthedath Vellarikkal ◽  
Arghya Sett ◽  
Sridhar Sivasubbu ◽  
Vinod Scaria ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Human Breast Cancer ◽  
Estrogen Receptor Alpha ◽  
Human Breast ◽  
Altered Expression ◽  
Receptor Alpha

Co-expression of drug metabolizing cytochrome P450 enzymes and estrogen receptor alpha (ESR1) in human liver: racial differences and the regulatory role of ESR1

2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Joseph M. Collins ◽  
Danxin Wang
Keyword(s):  
Estrogen Receptor ◽  
Cytochrome P450 ◽  
Human Liver ◽  
Estrogen Receptor Alpha ◽  
Racial Difference ◽  
Partial Least Square ◽  
Mrna Levels ◽  
Altered Expression ◽  
Receptor Alpha ◽  
Cyp Enzymes

Abstract Objectives The function and expression of cytochrome P450 (CYP) drug metabolizing enzymes is highly variable, greatly affecting drug exposure, and therapeutic outcomes. The expression of these enzymes is known to be controlled by many transcription factors (TFs), including ligand-free estrogen receptor alpha (ESR1, in the absence of estrogen). However, the relationship between the expression of ESR1, other TFs, and CYP enzymes in human liver is still unclear. Methods Using real-time PCR, we quantified the mRNA levels of 12 CYP enzymes and nine TFs in 246 human liver samples from European American (EA, n = 133) and African American (AA, n = 113) donors. Results Our results showed higher expression levels of ESR1 and six CYP enzymes in EA than in AA. Partial least square regression analysis showed that ESR1 is the top-ranking TF associating with the expression of eight CYP enzymes, six of which showed racial difference in expression. Conversely, four CYP enzymes without racial difference in expression did not have ESR1 as a top-ranking TF. These results indicate that ESR1 may contribute to variation in CYP enzyme expression between these two ancestral backgrounds. Conclusions These results are consistent with our previous study showing ESR1 as a master regulator for the expression of several CYP enzymes. Therefore, factors affecting ESR1 expression may have broad influence on drug metabolism through altered expression of CYP enzymes.

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