# Elucidating the role and regulation of periostin in therapy-induced chemoresistance in metastatic breast cancer

> **NIH NIH K01** · COLORADO STATE UNIVERSITY · 2020 · $123,442

## Abstract

Project Summary/Abstract
 Approximately 450,000 women succumb to breast cancer each year, making it the most common cause of
female cancer mortality globally, with the majority of these deaths resulting from metastatic disease. In the
treatment of metastases, the initial drug response rate is only about 50%, as compared to 90% observed in the
treatment of primary tumors. Furthermore, resistance to these systemic therapies typically develops more
quickly in the metastatic setting, thus emphasizing the critical need to improve our understanding of the
mechanisms governing development of drug resistance. While chemotherapy effectively eliminates tumor cells,
it has also been shown to simultaneously induce various counter-regulatory responses in the cells and tissues
of the host, which leads to the development of a protective environment that promotes survival of few
remaining tumor cells, often referred to as cancer stem cells (CSCs). Although numerous studies have focused
on tumor cell intrinsic mechanisms of drug resistance, there have been very few investigations into extrinsic
mechanisms of drug resistance mediated by these changes in the host cells and tissue environment.
 Periostin (POSTN) is a structural support protein found during normal tissue development, but whose
expression has also been shown to be increased in cancer development and metastasis. During metastasis,
POSTN enhances the pro-survival Wnt and Akt signaling pathways in tumor cells to prevent stress-induced
apoptosis and increase the number of CSCs for promotion of early metastatic colonization of tissues.
Importantly, the production of POSTN is predominately induced by TGF-β, a molecule that is up regulated in
the tumor environment following exposure to chemotherapy. Based on these observations, we hypothesize
that POSTN production in response to chemotherapy induces a protective, pro-survival environment within
established metastases through induction of a CSC phenotype via activation of Wnt and\or Akt signaling
pathways, and that POSTN production is regulated primarily by TGF-β from tumor-associated macrophages
(TAMs). To answer these questions, we propose 3 specific aims, which we anticipate will fill a critical
knowledge gap regarding therapy-induced changes within the metastatic tumor environment, revealing a
significant role for POSTN in mediating acquired drug resistance in the metastatic setting. In Aim 1, we will
use organotypic lung-like cultures to identify the cytotoxic drug(s) that most strongly induce POSTN-mediated
chemoresistance in human breast cancer cells. We will determine if this resistance is mediated through
activation of the Wnt and\or Akt signaling pathways and induction of a CSC phenotype using western blot and
flow cytometry. For aim 2, we will use mouse models of breast cancer metastasis to identify the key cytokines
and their cellular sources regulating POSTN production within established metastases following chemotherapy.
This will be accomplishe...

## Key facts

- **NIH application ID:** 9926128
- **Project number:** 5K01OD022982-05
- **Recipient organization:** COLORADO STATE UNIVERSITY
- **Principal Investigator:** Daniel Patrick Regan
- **Activity code:** K01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $123,442
- **Award type:** 5
- **Project period:** 2016-07-01 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9926128

## Citation

> US National Institutes of Health, RePORTER application 9926128, Elucidating the role and regulation of periostin in therapy-induced chemoresistance in metastatic breast cancer (5K01OD022982-05). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9926128. Licensed CC0.

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