microRNA regulation of mammalian target of rapamycin expression and activity controls estrogen receptor function and RAD001 sensitivity

Molecular Cancer

Research

Lyndsay V Rhodes¹  Steven Elliott¹  Adrienne E Krebs¹  Elizabeth C Martin¹  Bridgette M Collins-Burow¹  Matthew E Burow²  Erik K Flemington³  Kenneth P Nephew⁴ 

[1] Department of Medicine-Section of Hematology and Medical Oncology, Tulane University, New Orleans, LA, USA;Department of Medicine-Section of Hematology and Medical Oncology, Tulane University, New Orleans, LA, USA;Department of Pharmacology, Tulane University, New Orleans, LA, USA;The Center for Bioenvironmental Research, Tulane University, New Orleans, LA, USA;Department of Pathology, Tulane University, New Orleans, LA, USA;Medical Sciences and Department of Cellular and Integrative Physiology, Indiana University School of Medicine, Bloomington, IN, USA;

关键词: miR-155;    mTOR;    breast cancer;    miRNA;    Estrogen receptor;   

DOI  :  10.1186/1476-4598-13-229

 received in 2014-05-28, accepted in 2014-09-24,  发布年份 2014

来源: Springer

【 摘 要 】

BackgroundThe AKT/mammalian target of rapamycin (mTOR) signaling pathway is regulated by 17α-estradiol (E2) signaling and mediates E2-induced proliferation and progesterone receptor (PgR) expression in breast cancer.Methods and resultsHere we use deep sequencing analysis of previously published data from The Cancer Genome Atlas to demonstrate that expression of a key component of mTOR signaling, rapamycin-insensitive companion of mTOR (Rictor), positively correlated with an estrogen receptor-α positive (ERα+) breast tumor signature. Through increased microRNA-155 (miR-155) expression in the ERα+ breast cancer cells we demonstrate repression of Rictor enhanced activation of mTOR complex 1 (mTORC1) signaling with both qPCR and western blot. miR-155-mediated mTOR signaling resulted in deregulated ERα signaling both in cultured cells in vitro and in xenografts in vivo in addition to repressed PgR expression and activity. Furthermore we observed that miR-155 enhanced mTORC1 signaling (observed through western blot for increased phosphorylation on mTOR S2448) and induced inhibition of mTORC2 signaling (evident through repressed Rictor and tuberous sclerosis 1 (TSC1) gene expression). mTORC1 induced deregulation of E2 signaling was confirmed using qPCR and the mTORC1-specific inhibitor RAD001. Co-treatment of MCF7 breast cancer cells stably overexpressing miR-155 with RAD001 and E2 restored E2-induced PgR gene expression. RAD001 treatment of SCID/CB17 mice inhibited E2-induced tumorigenesis of the MCF7 miR-155 overexpressing cell line. Finally we demonstrated a strong positive correlation between Rictor and PgR expression and a negative correlation with Raptor expression in Luminal B breast cancer samples, a breast cancer histological subtype known for having an altered ERα-signaling pathway.ConclusionsmiRNA mediated alterations in mTOR and ERα signaling establishes a new mechanism for altered estrogen responses independent of growth factor stimulation.

【 授权许可】

Unknown   
© Martin et al.; licensee BioMed Central Ltd. 2014. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.