# Investigating the biology and therapeutic vulnerabilities of ER+ metastatic breast cancer with activating HER2 mutations

> **NIH NIH K22** · JOHNS HOPKINS UNIVERSITY · 2021 · $195,220

## Abstract

Project
Summary/Abstract
The candidate, Ms. Utthara Nayar, PhD, is a translational cancer biologist, and currently a Research Fellow in
Medicine at Dana-Farber Cancer Institute, Harvard Medical School, and the Broad Institute of MIT and
Harvard. She employs genomic technology to investigate mechanisms of resistance in estrogen receptor-
expressing (ER+) metastatic breast cancer (MBC). Prior to this, she trained in viral oncology laboratories at
Cornell University and Brigham and Women's Hospital. She expects to pursue an academic career at the
intersection of basic and translational research in breast cancer that will involve molecular and genomic
approaches, in collaboration with physician-scientists and computational biologists working to end the disease.
This proposal lays out a structured 3-year plan of research and coursework, including the acquisition of data
science, grant-writing, and translational skills, which will uniquely situate the investigator as an experienced
experimental biologist and bioinformatician. The research project proposed, in combination with the team of
collaborators and institutional environment, is designed to position her on a road to independence within the
field of therapeutic response and resistance in breast cancer.
The primary reason for breast cancer mortality is the development of resistance, through largely unknown
mechanisms, to targeted anti-estrogen therapies in ER+ MBC. Dr. Nayar recently identified acquired activating
mutations in human epidermal growth factor receptor 2 (HER2), which activates the MAPK pathway, in patients
with resistance, and demonstrated that these directly conferred resistance to anti-ER agents. Since this is an
emerging class of resistance, a deeper understanding of the biology and therapeutic vulnerabilities of tumors
bearing such mutations or related genetic alterations in the MAPK pathway is required. The scientific objective
of this proposal is to study the effect of MAPK signaling from HER2 mutations in ER+ MBC in terms of two
major biological consequences that Dr. Nayar identified through global transcriptomic analysis in ER+ HER2-
mutant tumors: altered ER pathway, and enhanced interferon and inflammatory signaling. This application
proposes to investigate these questions in two distinct aims. In specific Aim 1, the effect of HER2 mutations on
the ER-associated and global transcriptional network will be examined using genome-scale in vitro approaches
(ChIP-seq/ATAC-seq). Aim 2 determines the implication of enhanced inflammatory signaling in ER+ HER2-
mutant tumors, by ascertaining the autocrine and paracrine effects on signaling and immunogenicity in cell line
and mouse model systems, as well as by examining tumor immune microenvironment in patient tumor
samples. At the end of the project, we can expect to gain a deeper understanding of HER2-mutant and related
breast tumors in terms of the effect of MAPK activation on ER signaling and immunogenicity, as well as their
potent...

## Key facts

- **NIH application ID:** 9977376
- **Project number:** 1K22CA241377-01A1
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Utthara Nayar
- **Activity code:** K22 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $195,220
- **Award type:** 1
- **Project period:** 2021-06-01 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9977376

## Citation

> US National Institutes of Health, RePORTER application 9977376, Investigating the biology and therapeutic vulnerabilities of ER+ metastatic breast cancer with activating HER2 mutations (1K22CA241377-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9977376. Licensed CC0.

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