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Profiling of Estrogen-regulated MicroRNAs in Breast Cancer Cells

Profiling of Estrogen-regulated MicroRNAs in Breast Cancer Cells

Published on: February 21, 2014

ERINA Is an Estrogen-Responsive LncRNA That Drives Breast Cancer through the E2F1/RB1 Pathway

Zihui Fang^1,2, Yue Wang¹, Zehua Wang¹

¹Center for Pharmacogenetics and Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, Pennsylvania.

Cancer Research

|August 23, 2020

Abstract:

Resistance to therapeutic drugs is a major challenge in the treatment of cancers, including breast cancer. Long noncoding RNAs (lncRNA) are known to have diverse physiologic and pathophysiologic functions, including in cancer. In searching for lncRNA responsible for cancer drug resistance, we identified an intergenic lncRNA ERINA (estrogen inducible lncRNA) as a novel lncRNA highly expressed in multiple cancer types, especially in estrogen receptor-positive (ER⁺) breast cancers. Expression of ERINA was inversely correlated with survival of patients with ER⁺ breast cancer and sensitivity to CDK inhibitor in breast cancer cell lines. Functional characterization established ERINA as an oncogenic lncRNA, as knockdown of ERINA in breast cancer cells inhibited cell-cycle progression and tumor cell proliferation in vitro and xenograft tumor growth in vivo. In contrast, overexpression of ERINA promoted cell growth and cell-cycle progression. ERINA promoted cell-cycle progression by interacting with the E2F transcription factor 1 (E2F1), which prevents the binding of E2F1 to the tumor suppressor retinoblastoma protein 1 (RB1). ERINA also functioned as an estrogen and ER-responsive gene, and an intronic ER-binding site was identified as an enhancer that mediates the transactivation of ERINA. In summary, ERINA is an estrogen-responsive oncogenic lncRNA that may serve as a novel biomarker and potential therapeutic target in breast cancer. SIGNIFICANCE: These findings identify ERINA as an estrogen-responsive, oncogenic lncRNA, whose elevated expression may contribute to drug resistance and poor survival of patients with ER⁺ breast cancer.

Insights

A novel long noncoding RNA, ERINA, is highly expressed in estrogen receptor-positive breast cancers and linked to poor survival and drug resistance. ERINA promotes cancer cell growth by interacting with E2F1, presenting a potential therapeutic target.

Area of Science:

Oncology
Molecular Biology
Genetics

Background:

Drug resistance is a significant obstacle in cancer treatment, particularly for breast cancer.
Long noncoding RNAs (lncRNAs) play critical roles in cancer development and progression.
Identifying novel molecular players in cancer drug resistance is crucial for improving patient outcomes.

Purpose of the Study:

To identify novel lncRNAs involved in cancer drug resistance.
To characterize the function and mechanism of the identified lncRNA, ERINA, in breast cancer.
To explore ERINA as a potential biomarker and therapeutic target for ER-positive breast cancer.

Main Methods:

Bioinformatic analysis to identify candidate lncRNAs.
Expression analysis in cancer cell lines and patient samples.
Functional studies including gene knockdown and overexpression.
Mechanism of action studies involving protein-protein interactions and gene regulation analysis.

Main Results:

A novel intergenic lncRNA, ERINA (estrogen inducible lncRNA), was identified and found to be highly expressed in multiple cancer types, especially ER-positive breast cancers.
ERINA expression inversely correlated with patient survival and sensitivity to CDK inhibitors in ER-positive breast cancer.
Knockdown of ERINA inhibited cancer cell proliferation and tumor growth, while overexpression promoted it.
ERINA promotes cell-cycle progression by interacting with E2F1, preventing its binding to RB1.
ERINA is an estrogen-responsive gene regulated by an intronic enhancer.

Conclusions:

ERINA is an oncogenic lncRNA that promotes cell-cycle progression and tumor growth in breast cancer.
ERINA's elevated expression is associated with poor survival and drug resistance in ER-positive breast cancer patients.
ERINA represents a promising novel biomarker and therapeutic target for ER-positive breast cancer.

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