# INVESTIGATING THE ROLE OF HSP90 IN SHAPING THE CONSEQUENCES OF BRCA1 MUTATIONS

> **NIH NIH F32** · UNIVERSITY OF TX MD ANDERSON CAN CTR · 2022 · $71,734

## Abstract

PROJECT SUMMARY
Mutations that inactivate DNA repair factors increase genome instability and cancer susceptibility. Predicting the
phenotypic effects of mutations is confounded by pervasive polymorphisms and elusive environmental modifiers.
This proposal will tackle this problem by utilizing a fundamental epigenetic mechanism that mediates gene-by-
environment interactions in biological systems, protein folding. Proteins must properly fold to function; this is
achieved with help from specialized proteins called protein-folding chaperones. In helping proteins fold and
function, the abundant chaperone HSP90 “buffers” (that is – mitigates) the effects of deleterious mutations.
Environmental stressors tax HSP90 availability within cells thus revealing cryptic phenotypes in a mutant-specific
way. However, the selectivity of HSP90 for cancer mutations remains poorly defined. Addressing this question
will enable preemptive identification of environmentally sensitive genotypes in the population as well as
stratification of cancer patients who would benefit from the use of HSP90 inhibitors. Indeed, HSP90 mediates
resistance in breast cancer cells by buffering a Breast Cancer Associated 1 (BRCA1) protein folding mutant.
Targeted inhibition of HSP90 restores cancer cell sensitivity to genotoxic agents and induces genome instability.
I hypothesize that HSP90 buffers a broad range of mutations in BRCA1, and in doing so renders the induction
of genome instability conditional upon environmental stressors that impair HSP90 function. I will test this
hypothesis by using a powerful approach based on next-generation functional genomics and classical
cytogenetics methodologies to: 1) evaluate chaperone binding as a classifier of BRCA1 missense mutant
severity in cancer patients, 2) determine the HSP90-buffered landscape of BRCA1 mutations, 3) determine how
HSP90 influences the conditional haploinsufficiency of BRCA1 heterozygotes. Each aim will utilize highly specific
HSP90 inhibitors administered at non-toxic doses to specifically target HSP90-buffered mutants and not wild-
type variant controls. I will engineer non-malignant and malignant cells to express HSP90-buffered BRCA1
mutants and measure the effects of HSP90 inhibition on genome stability and cell viability. This work will not only
reveal fundamental mechanisms shaping the manifestations of BRCA1 mutations, but will also establish a
practical approach to improve the efficacy of BRCA1 targeted therapies using HSP90 inhibition to exacerbate
the effects of HSP90-buffered genome instability mutations. This proposal will prepare me for a career as an
independent scientist investigating the molecular mechanisms through which cancer mutations perturb the
function of DNA repair complexes at single-molecule resolution. I have established a career committee of experts
who will train me in high-throughput systems biology and functional genomics, genome instability and cancer
biology, genome engineering, and single-mo...

## Key facts

- **NIH application ID:** 10370315
- **Project number:** 5F32CA253780-02
- **Recipient organization:** UNIVERSITY OF TX MD ANDERSON CAN CTR
- **Principal Investigator:** Brant Gracia
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $71,734
- **Award type:** 5
- **Project period:** 2021-04-01 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10370315

## Citation

> US National Institutes of Health, RePORTER application 10370315, INVESTIGATING THE ROLE OF HSP90 IN SHAPING THE CONSEQUENCES OF BRCA1 MUTATIONS (5F32CA253780-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10370315. Licensed CC0.

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