Argonaute 2 Expression Correlates with a Luminal B Breast Cancer Subtype and Induces Estrogen Receptor Alpha Isoform Variation.

ABSTRACT: Estrogen receptor alpha (ER?) signaling pathways are frequently disrupted in breast cancer and contribute to disease progression. ER? signaling is multifaceted and many ER? regulators have been identified including transcription factors and growth factor pathways. More recently, microRNAs (miRNAs) are shown to deregulate ER? activity in breast carcinomas, with alterations in both ER? and miRNA expression correlating to cancer progression. In this study, we show that a high expression of Argonaute 2 (AGO2), a translation regulatory protein and mediator of miRNA function, correlates with the luminal B breast cancer subtype. We further demonstrate that a high expression of AGO2 in ER?+ tumors correlates with a poor clinical outcome. MCF-7 breast cancer cells overexpressing AGO2 (MCF7-AGO2) altered ER? downstream signaling and selective ER? variant expression. Enhanced ER?-36, a 36 kDa ER? isoform, protein and gene expression was observed in vitro. Through quantitative polymerase chain reaction (qPCR), we demonstrate decreased basal expression of the full-length ER? and progesterone receptor genes, in addition to loss of estrogen stimulated gene expression in vitro. Despite the loss, MCF-7-AGO2 cells demonstrated increased estrogen stimulated tumorigenesis in vivo. Together with our clinical findings on AGO2 expression and the luminal B subtype, we suggest that AGO2 is a regulator of altered ER? signaling in breast tumors.

SUBMITTER: Conger AK 

PROVIDER: S-EPMC5831908 | biostudies-other | 2016 Sep

REPOSITORIES: biostudies-other