Analysis of the Estrogen Receptor-Associated LncRNA Landscape Identifies a Role for ERLC1 in Breast Cancer Progression

Abstract

Estrogen receptor alpha (ERα) plays a vital role in the development of normal breast tissue and in breast cancer. By cross-analyzing The Cancer Genome Atlas (TCGA) database, ERα-regulated long noncoding RNA 1 (ERLC1) was identified as a long noncoding RNA exhibiting a strong association with ERα signaling and high specificity of expression in breast tissue. ERLC1 was transcriptionally activated by ERα, and ERLC1 stabilized the ESR1 transcript by sequestering miR-129 and tethering FXR1 to maintain a positive feedback loop that potentiated ERα signaling. ERLC1 was elevated in tamoxifen-resistant breast cancer cells, where ERLC1 depletion restored sensitivity to tamoxifen and increased the efficacy of palbociclib or fulvestrant therapy. Collectively, these data warrant further investigation of ERLC1 as a modulator of therapeutic response and potential therapeutic target in ER+ breast cancer. Significance: This study identifies an estrogen-regulated lncRNA and the mechanism by which it positively regulates ERα activity, demonstrating a feedback loop that can promote resistance to antiestrogen therapies in ER+ breast cancer.

Evaluating Dual-Targeted ECO/siRNA Nanoparticles against an Oncogenic lncRNA for Triple Negative Breast Cancer Therapy with Magnetic Resonance Molecular Imaging

“…lncRNA can regulate gene expression via chromatin modification, transcriptional, or post-transcriptional modifications and consequently impacts a variety of molecular targets . This property allows one lncRNA to have regulatory control across multiple levels, but it can be dysregulated in a tissue- and disease-specific manner. − Differentiation antagonizing noncoding RNA (DANCR) is an oncogenic lncRNA overexpressed in triple negative breast cancer (TNBC), an aggressive breast cancer subtype that lacks expression of hormone receptors and suitable drug targets. DANCR is known to increase cell proliferation and invasion in TNBC. − Because lncRNA is considered as an undruggable target for conventional therapeutics, RNA interference (RNAi) with small interfering RNA (siRNA) is an effective approach for regulating lncRNA for cancer therapy.…”

“… 2 This property allows one lncRNA to have regulatory control across multiple levels, but it can be dysregulated in a tissue- and disease-specific manner. 3 − 6 Differentiation antagonizing noncoding RNA (DANCR) is an oncogenic lncRNA overexpressed in triple negative breast cancer (TNBC), an aggressive breast cancer subtype that lacks expression of hormone receptors and suitable drug targets. DANCR is known to increase cell proliferation and invasion in TNBC.…”

Non-Coding RNAs Modulating Estrogen Signaling and Response to Endocrine Therapy in Breast Cancer

“…In the last few years, an increasing amount of evidence has demonstrated a role for lncRNAs in estrogen signaling and therapy response. A recent study reported that the lncRNA ERLC1 (ERα-regulated long noncoding RNA 1) counteracted ERα downregulation by miR-129 and tethered FXR1, resulting in a positive feedback loop that potentiated ERα signaling which, in turn, led to cellular resistance to tamoxifen and fulvestrant [ 105 ]. Another recent study reported that lncRNA LINP1 downregulated ERα expression, and although the mechanisms of this interaction remain to be elucidated, this lncRNA was shown to confer tamoxifen resistance to BC cells.…”