# Evaluation of molecular determinants of racial disparity in triple-negative breast cancer

> **NIH NIH R01** · JOHNS HOPKINS UNIVERSITY · 2021 · $374,578

## Abstract

PROJECT SUMMARY/ABSTRACT
Triple negative breast cancer (TNBC) is a very aggressive subtype with limited therapeutic options. Intriguingly,
women of African American (AA) origin have much higher TNBC-related mortality rates compared to European
American (EA) women. This difference is evident even after adjusting for socioeconomic status and access to
care, indicating a biological basis. TNBC tumors in AA women exhibit higher rate of growth and metastasis in
comparison to TNBC in EA women. There is an urgent need to understand the molecular mechanisms involved in
aggressive progression and increased metastatic potential of AA-TNBC. In our preliminary studies, we observed
that AA-TNBC cells have higher invasion and migration potential in comparison to EA-TNBC cells showing
inherently aggressive nature of AA-TNBC. In a preliminary screen, we found that a large percentage of AA-TNBC
tumors exhibit loss-of-tumor suppressor Liver Kinase B1 (LKB1) in comparison to EA-TNBC tumors. Our
preliminary microarray studies also found that LKB1-loss in AA-TNBC results in activation of oncoproteins- YAP
and TAZ. Our data suggest that with inherent loss of LKB1, AA-TNBC gain `an oncogenic input' in the form of
activated YAP-TAZ signaling. Using in vitro studies, clinical AA-TNBC and EA-TNBC samples and patient-derived
xenograft (PDX) models, we will test our hypothesis that inherent LKB1-loss in AA-TNBC results in activation of
oncogenic YAP-TAZ signaling leading to aggressive progression and increased metastatic potential of AA-TNBC.
Our novel findings also suggest that AA-TNBC tumors may be vulnerable to therapeutic strategies directed at
YAP-TAZ inhibition. Based on our strong preliminary data, we will investigate how loss of LKB1 in AA-TNBC might
lead to acquisition of higher YAP-TAZ, and drive growth and metastasis of AA-TNBC cells. We will also analyze
AA-TNBC and EA-TNBC tumors to establish LKB1-loss and elevated YAP-TAZ as biomarkers of aggressive
progression of AA-TNBC. We will utilize these biological insights to test and propose safe and effective therapeutic
strategies to target AA-TNBC. Using patient-derived xenograft (PDX) models, we propose to investigate whether
AA-TNBCs are particularly susceptible to YAP-TAZ inhibition strategies and whether currently clinically available
drugs (screened from a drug library) can be repurposed to target YAP-TAZ in AA-TNBC. Secondly, we plan to
examine whether Honokiol, a natural compound from Magnolia grandiflora, (selected from a screen of known
bioactive compounds) and its novel analogs have the potential to inhibit YAP-TAZ in AA-TNBC. Our studies will
provide new understanding how loss-of-LKB1 and gain-of-YAP-TAZ in AA-TNBC form a relentless axis that drives
AA-TNBC. These studies will provide novel insight into molecular mechanisms underlying racial disparity in TNBC
and provide a novel set of biomarkers and potential drug-targets to develop novel ways to reduce the disparity in
clinical outcome of AA and EA TNB...

## Key facts

- **NIH application ID:** 10158022
- **Project number:** 5R01CA204555-05
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Dipali Sharma
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $374,578
- **Award type:** 5
- **Project period:** 2017-05-17 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10158022

## Citation

> US National Institutes of Health, RePORTER application 10158022, Evaluation of molecular determinants of racial disparity in triple-negative breast cancer (5R01CA204555-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10158022. Licensed CC0.

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