# Rewiring of regulatory networks in breast cancer by transcription factor isoforms

> **NIH NIH U01** · DANA-FARBER CANCER INST · 2021 · $1,002,944

## Abstract

Project summary
One of the ultimate goals of cancer systems biology is to generate predictive and dynamic models of
tumorigenesis by identifying and quantifying all perturbed functional interactions in a cancerous cellular system.
The central hypothesis of this CSBC U01 application is that, among the combined effects of multiple types of
functional perturbations, those emerging from cancer-specific gene expression of alternative isoforms are
crucial for tumorigenesis. Genome alterations such as amplification, deletion, translocations and mutations, are
often considered primary events of cancer progression. However, cancer-specific isoforms resulting from
alternative splicing, alternative sites of transcriptional initiation, and/or alternative transcriptional termination
sites, have also been shown to have functional impact on tumorigenesis.
In particular, changes in gene regulatory networks (GRNs) by transcription factor (TF) isoforms have been
shown to play a major role in tumorigenesis and metastasis in multiple types of cancer. While a few examples
of functional characterization of driver cancer-specific TF isoforms have been reported, what remains unclear
is the extent to which differences in TF isoforms between normal and cancer tissue affect global GRNs and
how such regulatory network rewiring leads to altered gene expression programs in cancer. Indeed, hundreds
of differential TF isoforms have been identified between normal and cancer samples, but the vast majority
remain uncharacterized at the functional level.
In this project, we propose an initial step toward this long-term goal, which consists of characterizing and
modeling the effect of large numbers of breast cancer-specific TF isoforms in the context of cancer interactome
networks. We aim to combine network modeling and high-throughput systematic experimental strategies at the
level of molecular protein-protein and protein-DNA interactions to predict cancer drivers and suppressors. The
resulting hypotheses will be tested experimentally using various large-scale functional assays in breast cancer
as a model system. As part of the experimental testing, we will establish state-of-the-art genome editing
methodologies for testing the effects of isoform-specific perturbations on GRNs in mammalian cells.
Altogether, this project will constitute an important step towards the long-term goal of contextualizing and
functionalizing large numbers of TF isoforms implicated in breast cancer. Further, the lessons learned from the
data analysis and integration will lead to the identification of novel cancer drivers and suppressors, the
generation of mechanistic models of GRN rewiring in cancer, and provide a framework for the design of novel
therapeutics.

## Key facts

- **NIH application ID:** 10249199
- **Project number:** 5U01CA232161-04
- **Recipient organization:** DANA-FARBER CANCER INST
- **Principal Investigator:** MARTHA L BULYK
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $1,002,944
- **Award type:** 5
- **Project period:** 2018-09-17 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10249199

## Citation

> US National Institutes of Health, RePORTER application 10249199, Rewiring of regulatory networks in breast cancer by transcription factor isoforms (5U01CA232161-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10249199. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*