# The oncogenic role of EPIC1MYC axis in breast cancer

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2020 · $357,994

## Abstract

A better understanding of the molecular events that contribute to the aggressiveness and poor outcome of breast
cancer is essential to develop more effective therapies for this deadly disease. Emerging evidence suggests that
lncRNAs play important roles in breast cancer tumorigenesis. However, research of lncRNAs in breast cancer is
still in its infancy. Through an integrated bioinformatic analysis of the lncRNA epigenetic landscape in 6475 tumor
samples and 781 cancer cell lines, we discovered a novel intergenic lncRNA, EPIC1 (EPigenetically Induced
lnCRNA1, or ENSG00000224271). EPIC1 is significantly overexpressed in the luminal B breast cancer subtype
due to the loss of DNA methylation at the EPIC1 gene promoter. We went on to show that EPIC1 promotes
luminal B breast cancer tumorigenesis in cell cultures and in mouse xenograft models by directly interacting with
the oncogenic transcription factor MYC. In this project, we hypothesize that EPIC1 is an oncogenic lncRNA in
breast cancer, particularly in the luminal B subtype. Mechanistically, EPIC1 enhances the transcriptional activity
of MYC by directly interacting with the MYC protein. We propose three specific aims to test this hypothesis. In
Aim 1, we will characterize the EPIC1-MYC interaction using HITS-CLIP assay and investigate if the identified
MYC binding sequences in EPIC1 are necessary and sufficient for EPIC1-MYC interaction. We will also
determine the functional domain of MYC protein responsible for the EPIC1 binding. In Aim 2, we will determine
the oncogenic role of the EPIC1-MYC axis in breast cancer by overexpressing wt-EPIC1 or MYC binding
sequence deletion mutant EPIC1 (ΔMYC-EPIC1) in ZR-75-1 and BT-474 cells. We will then determine the
dependency of EPIC1’s oncogenic role on MYC protein in xenograft mouse models. Finally, we will investigate
EPIC1’s association with breast cancer clinical characteristics and outcomes in eight independent patient cohorts
including 1882 breast cancer tumors. In Aim 3, we will first determine the pattern of MYC binding to its target
gene promoters in wt- or ΔMYC-EPIC1 overexpressing ZR-75-1 and BT-474 cells by performing RNA-seq and
MYC ChIP-seq. We will then determine whether EPIC1 regulates the MYC targets through EPIC1-MYC binding
sites using ChIP-PCR and luciferase reporter analyses. Finally, we will construct the EPIC1-cMYC regulatory
network in breast cancer by integrating ChIP-seq, RNA-seq, and TCGA breast cancer data. Our study will
uncover the role of a novel oncogenic lncRNA, EPIC1, in breast cancer through its functional crosstalk with the
well-established oncogene MYC.

## Key facts

- **NIH application ID:** 9981699
- **Project number:** 5R01CA222274-03
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Da Yang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $357,994
- **Award type:** 5
- **Project period:** 2018-08-02 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9981699

## Citation

> US National Institutes of Health, RePORTER application 9981699, The oncogenic role of EPIC1MYC axis in breast cancer (5R01CA222274-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9981699. Licensed CC0.

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