# MDC1: central regulator of estrogen receptor function and therapy response in lobular carcinoma

> **NIH NIH R01** · UNIVERSITY OF COLORADO DENVER · 2023 · $348,592

## Abstract

PROJECT SUMMARY / ABSTRACT
Invasive lobular carcinoma (ILC) is an understudied subtype of breast cancer. Clinical and epidemiological
features of ILC are consistent with an exquisite dependence on estrogen and estrogen receptor alpha (ER),
and ILC biomarkers suggest that patients should have good outcomes with anti-estrogen treatment. However,
recent studies show that relative to other breast cancers, ILC patients have poorer long-term outcomes, have
poorer response to anti-estrogen therapy, and also do not benefit from chemotherapy. New treatments are
needed to improve ILC patient outcomes. However, advances are hindered by a fundamental lack of
understanding of the distinct biology of ILC, in particular regarding ER signaling. We and others identified de
novo anti-estrogen resistance in ILC models, and see that ER in ILC cells is activated by tamoxifen and next-
generation ER antagonists. Based on these observations, the limited efficacy of anti-estrogens in treating ILC
may be due to differences in ER function in ILC. Our work has identified unique ER functions in ILC, including
ILC-specific ER target genes, ER DNA binding, and ER signaling pathways, which in part explain endocrine
response and resistance. As a basis for these unique ER functions and anti-estrogen resistance in ILC, we
identified mediator of DNA damage checkpoint 1 (MDC1) as a novel transcriptional co-regulator of ER in ILC
cells. MDC1 is a cornerstone of DNA damage response, but in ILC, MDC1 acts as an ER co-regulator and is
required for ER-driven growth and ER regulation of key target genes, as well as anti-estrogen resistance. Our
data indicate that MDC1 regulates ER at least in part through epigenomic remodeling. MDC1 ER co-regulator
functions interplay with canonical roles of MDC1 in DNA damage response, implicating these functions in
clinical chemoresistance in ILC. The objective of this proposal is to define how MDC1 controls ER-driven gene
regulation and how ER:MDC1 mediates DDR functions in ILC cells. Our central hypothesis is that MDC1 is a
critical ER co-regulator mediating ER target gene regulation in ILC, creating targetable cross-talk between ER
and DNA damage response. In this study, we will: i) Define how ER and MDC1 interact to build a gene
regulation complex; ii) Define how ER and MDC1 influence their collective genome interactions; iii) Define the
DNA damage response that is associated with ER and MDC1 function. This project will lead to mechanistic
understanding of MDC1-driven ER functions in ILC, and link the unique functions of ER in ILC to new precision
treatment strategies using DDR inhibitors. Defining the role of MDC1 will also provide insight into the unique
ER-dependent etiology of ILC. This proposal will advance translational study of MDC1 by identifying ER:MDC1
biomarkers and therapeutic strategies to target MDC1-related DDR dependencies. Characterizing the role of
MDC1 is critical to understand ILC biology and improve outcomes for patients with I...

## Key facts

- **NIH application ID:** 10690428
- **Project number:** 5R01CA251621-02
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** Matthew J Sikora
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $348,592
- **Award type:** 5
- **Project period:** 2022-09-01 → 2027-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10690428

## Citation

> US National Institutes of Health, RePORTER application 10690428, MDC1: central regulator of estrogen receptor function and therapy response in lobular carcinoma (5R01CA251621-02). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10690428. Licensed CC0.

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