# Integrin Regulation of Non-apoptotic Death in Breast Cancer

> **NIH NIH R01** · UNIV OF MASSACHUSETTS MED SCH WORCESTER · 2020 · $383,156

## Abstract

Summary
This proposal will examine the regulation and role of ferroptosis in epithelial and carcinoma biology.
Ferroptosis involves the accumulation of intracellular reactive oxygen species (ROS) leading to inactivation of
the lipid repair enzyme glutathione peroxidase 4 (GPX4) and the consequent increase in lipid peroxides that
causes cell death. Data obtained reveal that extracellular matrix (ECM)-detached mammary epithelial and
breast carcinoma cells undergo ferroptosis specifically in the absence of a6b4. Also, ECM-detached cells that
cluster are prone to ferroptosis in the absence of a6b4. In contrast, single cells undergo apoptosis if a6b4
expression is depleted. The ability of a6b4 to signal an anti-ferroptotic response in ECM-detached cells
appears to be dependent on F-actin-rich, cell-cell complexes and that a6b4 may nucleate the formation of
these complexes, which have been termed ‘ferroptosis resistance complexes’. It is hypothesized that a6b4
signaling under these conditions buffers an increase in lipid peroxidation that occurs as a result of ECM
detachment by maintaining the expression of GPX4, a lipid peroxidase, enabling the evasion of ferroptosis. It
is proposed that the mechanism involves the ability of a6b4 signaling to stabilize GPX4 mRNA and prevents its
decay in stress conditions by promoting N6-methyladenosine (m6A) RNA de-methylation. The first aim will
investigate how a6b4 signaling is activated in ECM-detached cells and its role in the formation of ferroptosis
resistance complexes. The second aim will determine that a6b4 signaling impacts the stability of GPX4 and
other mRNAs in response to ECM-detachment. This aim will also involve identifying the spectrum of mRNAs
that are stabilized by m6A-de-methylation upon ECM-detachment. The final aim will investigate the significance
of a6b4 regulation of GPX4 and evasion of ferroptosis in breast cancer using mouse models. This aim will
involve an unbiased approach to assessing the contribution of GPX4 to breast tumorigenesis and progression
by conditional deletion in a transgenic mouse model of triple-negative breast cancer. Analysis of these mice
will enable an assessment of the contribution of GPX4 to tumor initiation, growth and metastasis, including
circulating tumor cells, and its role in the evasion of ferroptosis in vivo. The novel and unanticipated
hypotheses to be addressed have the potential to open a new field of investigation with significant implications
for our understanding of both ferroptosis and tumor biology that could benefit the design and development of
therapies to impede metastasis.
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## Key facts

- **NIH application ID:** 9954007
- **Project number:** 5R01CA218085-03
- **Recipient organization:** UNIV OF MASSACHUSETTS MED SCH WORCESTER
- **Principal Investigator:** Arthur M Mercurio
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $383,156
- **Award type:** 5
- **Project period:** 2018-07-11 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9954007

## Citation

> US National Institutes of Health, RePORTER application 9954007, Integrin Regulation of Non-apoptotic Death in Breast Cancer (5R01CA218085-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9954007. Licensed CC0.

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