# Project 3: MANCR Mediates Epigenetic Mechanisms for Survival of Advanced Breast Cancer

> **NIH NIH P01** · UNIVERSITY OF VERMONT & ST AGRIC COLLEGE · 2021 · $320,519

## Abstract

SUMMARY
Long non-coding RNAs (lncRNAs) are epigenetic regulators of the chromatin organization supporting
cancer cell activities. There is a gap in the literature identifying the chromatin interactions that establish
the phenotype of invasive breast cancer (BCa) cells. We have characterized a lncRNA, we named
MANCR (Mitotically Associated Non-Coding RNA (Tracy K Mol Can Res 2018) which is highly expressed in
aggressive triple negative and tamoxifen resistant (TAMR) BCa cell lines and increases further during
mitosis. Of clinical significance, MANCR inhibition results in cell death, thus having potential as a
therapeutic target to prevent invasive tumor growth. To reach this translational goal requires a complete
understanding of mechanisms by which MANCR is suppressed in non-malignant cells and activated in
activated in aggressive cancer cell and suppressed in normal mammary epithelial cells (NMEs). Our
findings support the hypothesis that MANCR alters the epigenetic environment via chromatin
interactions with genomic regions that support survival mechanisms in invasive breast cancer cells;
and that inhibition of MANCR will contribute to cell death and regression of tumors in vivo. The specific
aims are designed to obtain mechanistic insight at multiple levels to determine the MANCR functions
that sustain the aggressive cell phenotype. Aim1 identifies chromatin organization mediated by
MANCR’s epigenetic properties that support BCa survival by using: i) ChIRP-Seq to reveal MANCR
target gene binding sites at specific genomic locations; ii) ATAC-seq to obtain a map of accessible
chromatin regions that will identify genomic regulatory in aggressive MDA-231 cell supporting cell
survival and comparing to those domains altered by MANCR knockdown which will reveal mechanisms
resulting in cell death; iii) Capture Hi-C will discover the 3-dimensional chromatin interactions
contributing to survival of invasive BCa cells. Aim 2 focuses on mechanisms contributing to MANCR
suppression in NMEs and MCF7 ER+ BCa cells. We will i) examine if MANCR suppression is mediated
by estrogen signaling in ER+ cells, ii) examine MANCRs effect on TAMR; and iii) show that MANCR
suppression in normal mammary epithelial cells is mediated by the tumor suppressor RUNX1. Aim 3
will use two in vivo models: i) a pre-clinical xenograft mouse to demonstrate MDA-231 CRISPR inhibited
tumors in the mammary fat pad will become necrotic due to cell death; ii) resected BCa tumor tissue
that is MANCR positive to grow organoids for transplantation into mammary fat pad to determine if high
MANCR organoids have aggressive tumor growth compared to low expressing MANCR organoids.
Impact: MANCR expression correlates with poor prognosis and survival, its inhibition results in cell
death and MANCR is nearly absent from all normal tissues except testis and spleen. These properties
indicate MANCR’s potential as a therapeutic target to inhibit primary tumor growth of advanced BCa.

## Key facts

- **NIH application ID:** 10107343
- **Project number:** 1P01CA240685-01A1
- **Recipient organization:** UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
- **Principal Investigator:** Jane B. Lian
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $320,519
- **Award type:** 1
- **Project period:** 2021-04-01 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10107343

## Citation

> US National Institutes of Health, RePORTER application 10107343, Project 3: MANCR Mediates Epigenetic Mechanisms for Survival of Advanced Breast Cancer (1P01CA240685-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10107343. Licensed CC0.

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