# Targeting BUB 1 for radio- and immuno-sensitization of Triple Negative Breast Cancer (TNBC)

> **NIH NIH R21** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2021 · $401,117

## Abstract

PROJECT SUMMARY-ABSTRACT
Background: Breast cancer is the number one killer of women between the ages of 44 and 55 in this country.
It is estimated that more than 276,480 women will be newly diagnosed with breast cancer in 2020 and about
42,170 women are expected to die of breast cancer (BC) this year. Although ER+ tumors can be effectively
treated, there are no effective therapies available for ER- and specially triple negative breast cancers (TNBC).
TNBC accounts for 30% of all BC, is more aggressive and less responsive to treatment thus has highest mortality
rates. Currently, there are no molecular therapies approved for TNBC which could be combined with radio- or
immunotherapies.
Objective: Mechanisms of radioresistance are poorly understood, and immunotherapy has been largely
disappointing, but improvement of either could significantly impact outcomes for women with TNBC. Thus,
identifying drivers of radioresistance and immune regulation that can be effectively targeted represents a critical
unmet clinical need. The objective of this proposal is to establish BUB1 as a viable molecular target for
radiosensitization and immune priming as well as for predicting therapeutic outcome in TNBC.
Hypothesis: In an effort to identify actionable molecular targets for radiation- and immune- sensitization of TNBC,
we have identified BUB1 expression as a strong prognostic correlate of aggressive disease and poor clinical
outcome. We hypothesize that BUB1 mediates radioresistance and that BUB1 inhibition will sensitize resistant
TNBC to ionizing radiation. Furthermore, we hypothesize that BUB1 regulates TGFβ signaling in tumor
microenvironment leading to an increase in myeloid derived suppressor cells (MDSCs) population, decrease in
cross-priming and immunotherapy resistance. We propose that genomic depletion or inhibition of BUB1 will
reduce TGFβ and MDSCs, and will ascertain differentiation back to antigen presenting cells (APC) which will
restore innate immunity and make tumors sensitive to immune checkpoint blockade.
Impact: The proposed studies will validate BUB1 as a molecular target for TNBC therapy. This study will provide
rationale for targeting BUB1 in combination with radio- or immune-therapy and will provide conclusive pre-clinical
data for future clinical translation. We are certain that our approach of targeting BUB1 in combination with radio-
and immunotherapy is fundamentally better than the current therapies as it exploits the multiple functions of
BUB1 including cell-cycle, DNA- damage response and TGFβ signaling. We envision that the successful
completion of the proposed study will lead to new treatment paradigms that go beyond minor improvements and
will have major impact on breast cancer treatment, especially on TNBC.

## Key facts

- **NIH application ID:** 10196543
- **Project number:** 1R21CA252010-01A1
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Michael Daniel Green
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $401,117
- **Award type:** 1
- **Project period:** 2021-04-15 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10196543

## Citation

> US National Institutes of Health, RePORTER application 10196543, Targeting BUB 1 for radio- and immuno-sensitization of Triple Negative Breast Cancer (TNBC) (1R21CA252010-01A1). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10196543. Licensed CC0.

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