# Mechanisms of epigenetic regulation of estrogen receptor function in breast cancer

> **NIH NIH K22** · JOHNS HOPKINS UNIVERSITY · 2021 · $187,800

## Abstract

PROJECT SUMMARY/ ABSTRACT
CANDIDATE: My ultimate goal is to become a principal investigator focused on the epigenetic mechanisms
driving the pathogenesis of human diseases. I seek to attain a tenure-track position allowing me to establish a
research program that studies the epigenetic mechanisms driving breast cancer and the translation of basic
research findings into potential new therapies. To achieve my goal, I have developed a career development plan
with four key elements: 1) To expand and strengthen my experimental skills and scientific knowledge, 2) To
enhance my leadership, mentoring skills, and professional development, 3) To receive support on my career
transition from Dr. Ross Levine and research guidance and career support from my collaborators Drs. Maurizio
Scaltriti, Sarat Chanderlapaty, Minkui Luo, and Charles Sawyers, Ari Melnick and my advisers Drs. Larry Norton
and Ronglai Shen 4) To transition into a tenure-track research independent position.
ENVIRONMENT: The proposed study will be conducted at MSKCC, acknowledged for its exceptional patient
care, state-of-the-art facilities, and innovative research. I am part of the Human Oncology and Pathogenesis
Program (HOPP) that brings together scientists with an interest in mechanism-based laboratory and translational
research. Under the leadership of Dr. Charles Sawyers, HOPP creates a highly collaborative environment that
will greatly facilitate my translational research efforts.
RESEARCH: Alterations in the PI3K pathway occur in 40-60% of ER+ breast cancer or AR+ breast cancer,
representing the most common genomic alteration in such tumors, and indicating that the PI3K signaling pathway
plays an important role in the tumorigenesis of hormone-dependent tumors. There is important bidirectional
regulatory crosstalk between PI3K and ER or AR signaling in breast and prostate cancers respectively, leading
to tumors that adapt and survive when either single pathway is pharmacologically inhibited. I have recently
demonstrated that PI3K inhibition activates ER function to drive tumor growth in ER+/PIK3CA mutants, through
the epigenetic regulator KMT2D. We hypothesized that KMT2D could be a general mechanism in controlling
nuclear hormone receptor function and regulate the AR-PI3K crosstalk at cell-specific enhancers of prostate
cells. Preliminary data show that KMT2D is required for androgen response upon PI3K inhibition. We now aim
to study the molecular mechanisms of KMT2D in the regulation of AR-PI3K crosstalk using prostate cancer cell
lines and human prostate organoids (AIM 1 and 2). Furthermore, while searching for epigenetic regulators and
their involvement in therapeutic response in ER+ breast cancer, we have also conducted a CRISPR knockout
screen that identified the epigenetic regulator ARID1A as the top candidate whose loss mediates resistance to
anti-ER therapy through lineage switching. To this end, we aim to dissect the in vivo function and the chromatin-
based regulation of ARI...

## Key facts

- **NIH application ID:** 10055648
- **Project number:** 1K22CA245487-01A1
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Eneda Toska
- **Activity code:** K22 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $187,800
- **Award type:** 1
- **Project period:** 2021-06-16 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10055648

## Citation

> US National Institutes of Health, RePORTER application 10055648, Mechanisms of epigenetic regulation of estrogen receptor function in breast cancer (1K22CA245487-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10055648. Licensed CC0.

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