# Implications and Vulnerabilities of APOBEC Mutagenesis in Breast Cancer

> **NIH NIH R01** · SLOAN-KETTERING INST CAN RESEARCH · 2020 · $721,982

## Abstract

Summary: Although the majority of early stage estrogen receptor (ER)-positive breast cancers are cured through
multimodality care, metastatic ER-positive breast cancer remains a lethal disease. Insights into this discrepancy
have come through comparative genomic analyses of primary and metastatic tumors. We and others have
identified several mutations affecting specific genes that are more prevalent in metastatic cancers than in their
primary counterparts, including ESR1, ERBB2 and NF1. These mutations result in resistance to front-line
endocrine treatments that are the mainstay systemic therapy in ER-positive breast cancer. Even more striking
than such individual mutations, however, has been the finding that certain `mutational signatures' are enriched
in metastatic disease as compared to primary breast cancers. These mutational signatures represent the DNA
damage and repair processes that shape the cancer genome and can give rise to such mutations and the
transformed phenotypes they convey. A glaring and consistent finding from multiple large-scale sequencing
studies has been that the APOBEC mutational signature is both enriched and highly prevalent in ER-positive
metastatic disease, comprising the dominant mutational signature for these drug-resistant and ultimately lethal
cancers. Our preliminary data confirm that APOBEC activation can promote the development of endocrine
resistance in ER-positive cancer models and is associated with characteristic APOBEC-mutational changes in
many drug resistance alleles. Together, these results point to the APOBEC mutational process as a key driver
in the development and pathogenesis of ER-positive metastatic breast cancer and endocrine therapy resistance.
In this highly collaborative and innovative project, we propose three specific aims to advance the APOBEC
mutational process as a biomarker and therapeutic target in breast cancer. (1) We will develop and utilize robust
bioinformatic methods to detect the presence and the timing of onset of the APOBEC mutational signature from
clinical NGS datasets of both tumor and cell free DNA (cfDNA). We will further ascertain if a promising IHC assay
for the A3B enzyme can identify those ER-positive cancers likely to subsequently develop an APOBEC
mutational signature. (2) We will determine the mechanisms and kinetics of APOBEC's contribution to endocrine
resistance. We will use isogenic cell line models and patient derived xenografts to dissect the types of resistance
patterns that are caused by APOBEC as well their timing and whether the endocrine therapy itself contributes to
the induction of APOBEC activity. (3) We will assess both candidate and unbiased synthetic lethal approaches
to targeting tumors in which APOBEC activity is induced and determine their capabilities in killing APOBEC-
positive cells and preventing the development of endocrine resistance. We anticipate that our findings will
uniquely position our team to launch clinical trials testing specific ...

## Key facts

- **NIH application ID:** 9864860
- **Project number:** 1R01CA244812-01
- **Recipient organization:** SLOAN-KETTERING INST CAN RESEARCH
- **Principal Investigator:** Sarat Chandarlapaty
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $721,982
- **Award type:** 1
- **Project period:** 2020-02-15 → 2020-08-13

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9864860

## Citation

> US National Institutes of Health, RePORTER application 9864860, Implications and Vulnerabilities of APOBEC Mutagenesis in Breast Cancer (1R01CA244812-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9864860. Licensed CC0.

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