# Notch-driven Epigenetic Program of MYC and CCND1 in Triple-Negative Breast Cancer

> **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 2022 · $420,652

## Abstract

Project Summary
Triple-negative breast cancer (TNBC) accounts for ~10% of all the breast cancer cases, but its survival rate is
lower due to the lack of effective targeted treatments. This underscores the importance of finding new
treatments for therapy-resistant TNBC, which is further complicated by the disease heterogeneity.
Unfortunately, success of targeted therapies in TNBC has been limited, partly due to the lack of a detailed and
mechanistic understanding of the drivers of each disease subgroup. An important contributor to the TNBC
pathobiology is Notch signaling. Hyperactive Notch signaling promotes tumor growth, increases chemotherapy
resistance, decreases survival, and increases the chance of metastases. Although the biomarkers of the
Notch-active TNBC subgroup and drugs to target Notch signaling have been recently developed, treating
patients with Notch inhibitory agents has been ineffective to date, partly due to the limited understanding of
how the Notch signaling controls these fundamental processes.
 An important direct consequence of Notch signaling is to activate key TNBC genes, including MYC,
CCND1 and SOX9. MYC is one of the most important proto-oncogenes promoting tumor growth and survival.
CCND1 controls cell division among other cellular processes. SOX9 increases metastatic potential. Despite
their importance, existing drugs fail to directly target these proteins. We propose to leverage the regulatory
relationships between Notch and its target genes to selectively and efficiently target them. In order to achieve
this goal, we first need to understand the mechanisms by which Notch regulates MYC, CCND1, and SOX9 in
TNBC. We propose to use cutting-edge functional genomics and chromatin conformation assays to elucidate
their Notch-directed regulatory mechanisms at population and single-cell resolutions. To develop more potent
therapeutic options, we plan to use the latest single-cell resolution technologies to discover how drug-resistant
cells circumvent the effect of Notch inhibitory drugs and maintain the expression of these critical Notch targets.
We plan to use this knowledge in the future to tailor therapeutic strategies for individual TNBC patients with
activated Notch signaling, and in the process, hope to improve the survival of patients with this aggressive and
difficult to treat form of breast cancer.
!

## Key facts

- **NIH application ID:** 10302976
- **Project number:** 5R01CA230800-03
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Robert Babak Faryabi
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $420,652
- **Award type:** 5
- **Project period:** 2019-12-01 → 2025-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10302976

## Citation

> US National Institutes of Health, RePORTER application 10302976, Notch-driven Epigenetic Program of MYC and CCND1 in Triple-Negative Breast Cancer (5R01CA230800-03). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10302976. Licensed CC0.

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