# Targeting Chemotherapy-induced Breast Cancer Stemness

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2020 · $469,370

## Abstract

PROJECT SUMMARY/ABSTRACT
Preoperative or neoadjuvant therapy (NT) is increasingly used in patients with locally advanced or
inflammatory breast cancer (BC) to allow optimal surgery. Although a pathologic complete response has been
associated with increased survival, many patients do not respond and/or develop lethal metastatic disease
after NT. Our preliminary data indicate that chemotherapy induces blood levels of monocyte chemoattractant
proteins (MCPs), which can stimulate the cancer stem-like cell (CSC) phenotype to promote tumor malignancy.
The goal of this study is to dissect the mechanisms through which NT regimens induce the CSC
phenotype in breast tumors. We will investigate both a MCP-mediated systemic mechanism and a local
mechanism mediated by cancer-secreted miRNAs, and will test intervention strategies that block these events
during chemotherapy. The overall goal is to design interventions that maximize the beneficial effects of
anticancer treatment by preventing NT-induced CSC expansion. In Aim 1, we will first use human and
mouse BC cells to determine how receptor activation by MCPs leads to Numb degradation and Notch
activation to promote CSCs. Additional effectors mediating MCPs' effect on cancer cells will be identified.
Mouse tumor models will be used to determine the effect of MCPs on non-cancer cells in the tumor
microenvironment, which may in turn regulate the cytokine environment to influence CSCs. In Aim 2, we will
determine if the chemotherapy-induced miRNAs identified in our preliminary study synergistically stimulate
CSCs with systemically elevated MCPs. In Aim 3, patient-derived xenograft tumor models and mouse tumor
models will be used to determine the anti-CSC effects of various agents targeting the herein identified
pathways. We will then determine if NT induces monocyte expansion in BC patients and if MCP-initiated
signaling is associated with CSC frequency in primary human BCs. Results from the proposed work will
provide a mechanistic and pre-clinical basis for a future clinical trial using one of the CCR2 inhibitors previously
developed for non-cancer diseases to target treatment-induced CSCs in BC patients. Improving our
understanding of the interplay between hematopoietic cells, bulk cancer cells, and CSC populations after NT
will allow the development of improved combinatorial therapies to reduce therapeutic resistance and tumor
relapse. It may also provide insight into the clinical application of therapeutic regimens tailored to the need of
individual patients, ultimately leading to an increased success of anticancer treatment.

## Key facts

- **NIH application ID:** 9983624
- **Project number:** 5R01CA206911-04
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** Shizhen Emily Wang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $469,370
- **Award type:** 5
- **Project period:** 2017-08-01 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9983624

## Citation

> US National Institutes of Health, RePORTER application 9983624, Targeting Chemotherapy-induced Breast Cancer Stemness (5R01CA206911-04). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9983624. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*