# Role of Transcription Factor ADP-ribosylation in Breast Cancer Biology

> **NIH NIH R01** · UT SOUTHWESTERN MEDICAL CENTER · 2021 · $410,870

## Abstract

Project Summary/Abstract
 The molecular heterogeneity of cancers poses a major hurdle for treatment and drug discovery efforts.
Previous studies have addressed this challenge by characterizing distinct molecular subtypes of specific cancers
(e.g., breast cancers), based on cell type-specific patterns of gene expression. To interrogate the molecular
underpinnings of cancer subtypes, the Kraus Lab has developed a robust and multi-faceted computational
pipeline that integrates data from various genomic assays to define a Total Functional Score of Enhancer
Elements (TFSEE) for each subtype. One outcome of this method is the identification of cancer subtype-
enriched transcription factors (TFs) that promote subtype-specific enhancer formation and drive downstream
transcriptional outcomes. In breast cancers, several TFSEE-identified subtype-specific TFs are uniquely
required for the growth of the cognate breast cancer subtype, but do not affect the proliferation or viability of
other subtypes. Recent studies have also shown that ADP-ribosylation (ADPRylation), a post-translational
modification of proteins, varies dramatically across the different subtypes of breast cancers. ADPRylation is
mediated by the Poly(ADP-ribose) polymerase (PARP) family of enzymes, including PARP-1, a nuclear enzyme
which is the target of FDA-approved PARP inhibitor drugs. PARPs are well known for the roles in DNA repair,
but recent studies suggest an important BRCA1/2-independent role in transcriptional regulation as well. In
preliminary analyses, we have identified a cohort of cancer-related TFs that are ADPRylated in breast cancers.
 The long-term objective of these studies is to achieve a better understanding of the molecular and
biochemical mechanisms underlying the regulation of breast cancer subtype-specific TFs by ADPRylation, as
well as the responses of distinct breast cancer subtypes to PARP inhibitors. Our hypothesis is that ADPRylation
of subtype-specific TFs dictates their function and may influence the response of breast cancer cells to PARP
inhibitors. We have proposed a project that will use an integrated set of biochemical, molecular, cell-based,
mouse-based, genomic, and proteomic assays to test our overarching and specific mechanistic hypotheses.
Specifically, we will: (1) Identify TFs that are ADPRylated in breast cancers (Aim 1), (2) Determine how
ADPRylation of TFs affects their molecular and biochemical functions (Aim 2), and (3) Determine the effects of
TF ADPRylation on the responses of breast cancer cells to clinically used PARP inhibitors (Aim 3). These studies
will take advantage of the expertise of the PI’s lab in PARPs, ADPRylation, enhancer function, and gene
regulation in cancer. Although focused initially on breast cancers, our results should be broadly applicable across
a variety of cancer types. Our integrative approach using ‘omics’ and functional assays will provide new insights
into the regulation of TF ADP-ribosylation in breast cancers t...

## Key facts

- **NIH application ID:** 10209984
- **Project number:** 1R01CA251943-01A1
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** WILLIAM Lee KRAUS
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $410,870
- **Award type:** 1
- **Project period:** 2021-04-01 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10209984

## Citation

> US National Institutes of Health, RePORTER application 10209984, Role of Transcription Factor ADP-ribosylation in Breast Cancer Biology (1R01CA251943-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10209984. Licensed CC0.

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