# IRS2 and mitotic regulation in breast cancer

> **NIH NIH R01** · UNIV OF MASSACHUSETTS MED SCH WORCESTER · 2024 · $533,806

## Abstract

Project Summary
The overall goal of this proposal is to determine the mechanism by which Insulin Receptor Substrate 2 (IRS2)
regulates the spindle assembly checkpoint (SAC) and to use this information to study novel therapeutic
approaches for the treatment of triple negative breast cancer (TNBC). The IRS proteins are essential adaptor
proteins of the insulin (IR) and insulin-like growth factor-1 (IGF1R) receptors. Dysregulation of this pathway
through upregulation of receptors and ligands drives breast cancer initiation, growth and metastasis.
Unfortunately, interfering with the IIS pathway for the treatment of breast cancer by receptor/ligand-targeted
approaches has been unsuccessful, and efforts to improve the ability to target the IIS pathway for cancer therapy
are hindered by the fact that the mechanism(s) by which this signaling pathway contributes to cancer progression
are not well established. This proposal focuses on IRS2 because this adaptor protein is expressed preferentially
in TNBC, and the applicant has compelling data that IRS2 plays a causal role in the aggressive nature of this
breast cancer subtype. Understanding the mechanisms of action of IRS2 in TNBC is essential for exploiting IRS2
as a therapeutic target. In this regard, intriguing recent evidence from the applicant’s lab and other labs has
emerged that implicates IRS2 in mitotic regulation. Specifically, IRS2 expression increases during mitosis, and
it is required for cell cycle arrest at the spindle assembly checkpoint (SAC), a process that ensures precise
chromosomal segregation to maintain genome integrity. Importantly, no studies to date have established the
mechanistic role of IRS2 in SAC regulation. Toward this goal, the applicant has identified the cell cycle regulatory
kinase PLK1, which controls the SAC, as an IRS2-specific interacting protein. Together, these findings reveal a
potential IRS2-dependent vulnerability that could be exploited therapeutically, a possibility that is supported by
the applicant’s preliminary data that loss of IRS2 expression sensitizes TNBC to mitotic stress drugs. To
investigate the hypothesis that IRS2 regulation of the SAC sustains TNBC viability and that targeting this function
of IRS2 will inhibit tumor growth at both primary and metastatic sites, the applicant will: 1) Investigate the role of
IRS2 in spindle assembly checkpoint (SAC) regulation. The hypothesis that IRS2 expression and localization
are essential for efficient mitotic SAC activation will be examined; 2) Establish the molecular mechanisms by
which IRS2 regulates the mitotic SAC. The hypothesis that IRS2 promotes the fidelity of spindle formation
through the recruitment and activation of PLK1 will be examined; 3) Assess the therapeutic efficacy of targeting
IRS2-dependent cell cycle functions in TNBC. The hypothesis that acute targeting of IRS2 expression and/or its
cell-cycle regulatory functions will sensitize TNBC to mitotic stress will be examined.

## Key facts

- **NIH application ID:** 10996593
- **Project number:** 1R01CA290778-01A1
- **Recipient organization:** UNIV OF MASSACHUSETTS MED SCH WORCESTER
- **Principal Investigator:** LESLIE M SHAW
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $533,806
- **Award type:** 1
- **Project period:** 2024-09-01 → 2029-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10996593

## Citation

> US National Institutes of Health, RePORTER application 10996593, IRS2 and mitotic regulation in breast cancer (1R01CA290778-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10996593. Licensed CC0.

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