# Investigating mechanisms of chemoresistance in triple-negative breast cancer

> **NIH NIH R01** · TUFTS UNIVERSITY MEDFORD · 2022 · $347,192

## Abstract

Project Summary
Chemotherapy remains the standard of care for patients with triple-negative breast cancer (TNBC), which
affects 20% of patients with breast cancer. However, 50% of patients with localized TNBC treated with
neoadjuvant chemotherapy display residual cancer burden after treatment and up to 25% of patients who
receive this treatment will suffer metastatic recurrence within five years. The poor association between
chemotherapy and patient outcome emphasizes two major problems for TNBC patients: chemoresistance,
where tumor cells within the local environment are protected and do not die in response to chemotherapy, and
chemotherapy-induced metastasis, where chemotherapy-induced changes in tumor intrinsic properties and the
tumor microenvironment drive invasion which leads to recurrence. Previous studies have demonstrated that
cell migration and extracellular matrix (ECM) remodeling are associated with chemoresistant TNBC. The goal
of this proposal is to understand the mechanisms by which the ECM contributes to chemoresistance and
chemotherapy-induced metastasis in TNBC.
We provide preliminary data that individual proteins upregulated in TNBC tumors drive resistance to
chemotherapy drug Paclitaxel and that expression of Cathepsin B (CTSB), a protease which degrades these
ECM proteins into small fragments, protects against the development of chemoresistance. We will dissect the
mechanism by which the protease CTSB and the ECM proteins it degrades influence response to Paclitaxel in
TNBC and whether these fragments can be used to track and target chemoresistance in vivo. We have also
found that chemotherapy treatment leads to changes in the ECM composition of mammary tumors.
Specifically, Paclitaxel treatment leads to an increased abundance of Collagen IV, an ECM protein which
promote invasion and metastasis in TNBC. Our goal is to determine the cell types that secrete ECM proteins
such as Collagen IV after chemotherapy treatment, determine the contribution of these ECM proteins to
chemotherapy-induced metastasis, and whether these pathways can be targeted to prevent the development
of recurrence.
Upon successful completion of the proposed research, our contribution is expected to be an understanding of
how ECM proteins upregulated in TNBC tumors contribute to chemoresistance and how chemotherapy alters
the ECM to promote recurrence and metastatic dissemination. These contributions will be significant because
all TNBC patients receive chemotherapy and metastatic recurrence is a current unmet clinical need. Results
from these studies will provide novel conceptual insights on mechanisms of chemoresistance and
chemotherapy-induced metastasis and will allow us to develop new strategies to track, predict and overcome
chemoresistance in TNBC.

## Key facts

- **NIH application ID:** 10363559
- **Project number:** 1R01CA255742-01A1
- **Recipient organization:** TUFTS UNIVERSITY MEDFORD
- **Principal Investigator:** Madeleine Julie Oudin
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $347,192
- **Award type:** 1
- **Project period:** 2022-01-11 → 2026-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10363559

## Citation

> US National Institutes of Health, RePORTER application 10363559, Investigating mechanisms of chemoresistance in triple-negative breast cancer (1R01CA255742-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10363559. Licensed CC0.

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