# Heterogeneous Loss of GDF11 Tumor Suppression in Triple-negative Breast Cancer

> **NIH NIH R01** · UNIVERSITY OF VIRGINIA · 2020 · $360,746

## Abstract

PROJECT SUMMARY/ABSTRACT
Roughly 85% of triple-negative breast cancers are categorized as basal-like or claudin-low carcinoma,
molecular subtypes with especially poor prognosis and limited treatment options. Triple-negative breast
cancers frequently harbor mutations in DNA-surveillance pathways; consequently, their overall genomic
heterogeneity has been extensively characterized. By comparison, much less work has been done on the cell
biology of triple-negative breast cancer. Despite the recognized histological nonuniformity of triple-negative
tumors, we have only a rudimentary inventory of the types of signaling and transcriptional regulatory states that
single basal-like and claudin-low cells can adopt. The long-term goal of this work is to identify and characterize
the major cell-to-cell regulatory heterogeneities in triple-negative breast cancer. The current application
focuses on growth-differentiation factor 11 (GDF11), a diffusible factor that is heterogeneously regulated in 3D
organotypic cultures of claudin-low breast epithelial cells. Functional GDF11 bioactivity is lost in clinical cases
of advanced triple-negative breast cancer, and addition of GDF11 to invasive claudin-low and basal-like cancer
lines strongly suppresses invasion into basement membrane ECM. The hypothesis is that GDF11 acts a local
breast-epithelial cue for proper lobular architecture, which is suppressed nongenetically during triple-negative
breast cancer progression. The aims of this proposal are: 1) To identify the signaling and transcriptional
mechanisms that mediate GDF11-induced phenotypes in triple-negative breast cancer. 2) To define the key
steps of GDF11 misregulation in triple-negative neoplasms. 3) To determine the impact of GDF11 on
progression and metastatic colonization of triple-negative tumors. The diversity of regulatory states enables
triple-negative breast cancer cells to switch and adapt rapidly during tumor progression and the evolution of
drug resistance. A complete inventory of regulatory states and their transitions could one day be harnessed by
novel therapies that reset intratumor regulatory heterogeneity to delay progression or resistance.

## Key facts

- **NIH application ID:** 9840458
- **Project number:** 5R01CA214718-03
- **Recipient organization:** UNIVERSITY OF VIRGINIA
- **Principal Investigator:** Kevin A Janes
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $360,746
- **Award type:** 5
- **Project period:** 2018-01-01 → 2022-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9840458

## Citation

> US National Institutes of Health, RePORTER application 9840458, Heterogeneous Loss of GDF11 Tumor Suppression in Triple-negative Breast Cancer (5R01CA214718-03). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/9840458. Licensed CC0.

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