# TNBC in AA Women

> **NIH NIH R01** · CASE WESTERN RESERVE UNIVERSITY · 2020 · $197,603

## Abstract

Breast cancer is a heterogeneous disease comprised of at least 5 major tumor subtypes that coalesce as
the 2nd leading cause of cancer death in women in the United States. Amongst individual breast cancer
subtypes, triple-negative breast cancers (TNBCs) are clinically unique via their presentation of aggressive
phenotypes, and high propensity to recur rapidly following conventional chemotherapy treatment. TNBCs do
not express hormone receptors (estrogen and progesterone) and HER2, a phenotype that renders targeted
chemotherapies (e.g., hormonal or HER2-directed) ineffective and contributes to the poor prognosis of TNBC
patients. Although our understanding of the molecular features and clinical manifestations of TNBCs has
increased in recent years, science and medicine still lack sufficient knowledge of TNBC development and
metastasis to permit the synthesis of chemotherapies capable of specifically targeting this aggressive breast
cancer subtype. WAVE3 (W3) is a member of the WASP/WAVE family of actin-binding proteins and plays an
essential role in governing cell shape/morphology, actin polymerization and cytoskeleton remodeling, and cell
motility and invasion. Importantly, we showed that W3 expression is aberrantly elevated in TNBCs, and that
enforced expression of W3 promotes the acquisition of invasive, and metastatic phenotypes in TNBCs. Based
on these and other preliminary findings, we hypothesize that (i) c-Abl-mediated phosphorylation of WAVE3
promotes the aggressiveness of late-stage TNBCs; (ii) Interaction between WAVE3 and YBox1 (YB1), a
cancer stem cell-specific transcription factor, enhances the development and progression of TNBC tumors; and
(iii) cellular depletion of W3 expression sensitizes TNBCs to the anticancer and apoptotic activities of standard-
of-care chemotherapies. These hypotheses will be addressed by three Specific Aims. Aim 1 will determine the
role of c-Abl-mediated phosphorylation of W3 on TNBC development and progression. We will create c-Abl-
resistant W3 mutants and determine their ability to regulate TNBC tumorigenicity both in vitro and in vivo.
Likewise, mass-spectrometry analyses identified novel WAVE3-binding proteins, such as YB1. Aim 2 will
investigate the significance of the W3/YB1 interaction in promoting the development and metastatic
progression of TNBCs, and in the regulation of the transcription machinery of cancer stem cells, which will be
determined in in vitro and in vivo models of TNBCs. Aim 3 will use our newly developed ECO nanoparticles to
specifically deliver W3 inhibitors to TNBC tumors and determine the effectiveness of W3 inactivation to
restore/enhance the sensitivity of TNBCs to chemotherapy as a means to alleviate TNBC progression and
metastasis. Collectively, the findings obtained in this innovation application will provide novel molecular
insights into how W3 promotes TNBC tumorigenicity. They will also generate innovative translational outcomes
in the form of novel treatment options ...

## Key facts

- **NIH application ID:** 10104131
- **Project number:** 3R01CA226921-03S1
- **Recipient organization:** CASE WESTERN RESERVE UNIVERSITY
- **Principal Investigator:** KHALID SOSSEY-ALAOUI
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $197,603
- **Award type:** 3
- **Project period:** 2018-12-01 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10104131

## Citation

> US National Institutes of Health, RePORTER application 10104131, TNBC in AA Women (3R01CA226921-03S1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10104131. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*