# Matrix density promotes pro-tumorigenic hormone actions in breast cancer

> **NIH NIH R01** · UNIVERSITY OF WISCONSIN-MADISON · 2022 · $473,371

## Abstract

ABSTRACT
Although many women with estrogen receptor positive (ER+) primary cancers are successfully
treated with surgery and adjuvant anti-estrogen therapies, metastatic therapy-resistant ER+
cancers account for the majority of breast cancer related deaths. New understanding of the
biology underlying disease processes is required to develop new approaches. In this renewal
application, we build on our previous findings demonstrating dynamic reciprocity between
estrogen and features of the extracellular matrix (ECM) in the microenvironments of both the
primary tumor and the metastatic niche which fuel the pulmonary metastatic burden. We showed
that estrogen remodels the ECM architecture of the primary tumor, aligning collagen fibers and
increasing synthesis of ECM components associated with more aggressive cancers, and alters
ECM components in the lung metastatic niche. Moreover, we showed that this collagen alignment
signature in patient tumors correlates with inflammatory markers, including COX-2 and CD163+
macrophages, and poor prognosis. In the current proposal, we hypothesize that estrogen
orchestrates synergy among ER+ tumor cells, the extracellular matrix (ECM)/ cancer associated
fibroblasts (CAFs), and macrophages/ inflammation, to fuel primary and metastatic tumor
aggression. We will utilize our robust immunocompetent in vivo model of metastatic ER+ breast
cancer, in vitro systems, PDX models and clinical patient samples to test this hypothesis in the
following aims. Aim 1: Identify the steps in metastatic progression of ER+ breast cancer which
are altered by estrogen activity in tumor cells as well as other estrogen targets. Aim 2: Determine
how estrogen action on CAFs modifies the stromal ECM to mediate tumor progression, determine
the receptors that mediate this action, and identify ECM signatures from native stromal matrix
from ER+ invasive ductal carcinoma biopsies that instruct estrogen action on tumor cell growth
and migration. Aim 3: Determine how estrogen impacts immune metastatic mediators, including
macrophage activity and the inflammatory tumor microenvironment. Aim 4: Evaluate the ability of
standard of care therapeutic approaches to reverse E2-promoted steps in metastasis and post-
treatment estrogen re-exposure to promote growth of residual pulmonary lesions, and interrogate
the interrelationships among E2-altered ECM structure, and macrophage activity/inflammation.
Our studies will illuminate the role of estrogen in dissemination and pulmonary metastatic
colonization, with implications for therapy, metastatic dormancy and recurrence of ER+ breast
cancer, and reveal potential sites for intervention.

## Key facts

- **NIH application ID:** 10437643
- **Project number:** 5R01CA179556-08
- **Recipient organization:** UNIVERSITY OF WISCONSIN-MADISON
- **Principal Investigator:** Suzanne Marie Ponik
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $473,371
- **Award type:** 5
- **Project period:** 2014-04-01 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10437643

## Citation

> US National Institutes of Health, RePORTER application 10437643, Matrix density promotes pro-tumorigenic hormone actions in breast cancer (5R01CA179556-08). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10437643. Licensed CC0.

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