Breast cancers in African American (AA) women are characterized by earlier onset, higher aggressiveness, more extensive metastases, and increased mortality rates compared to those in European American (EA) women. This breast cancer-related health disparity is partly due to the fact that AA women are more likely than EA women to develop a particularly aggressive breast cancer subtype, called Triple-Negative Breast Cancer (TNBC). TNBC is characterized by fast progression to metastasis and high mortality rates. Furthermore, there are no targeted therapies for TNBC. Critical barriers to progress in improving outcomes for AA TNBC patients are (i) a lack of reliable risk-predictive biomarkers that can identify TNBCs at high risk of progressing rapidly to metastatic disease, and (ii) targeted therapies for TNBCs. Since tumor biology between AA and EA women with TNBC can vary greatly, the optimal way to combat TNBC may differ between AA and EA patients. Thus, it is critical to identify key biomarkers that may have special therapeutic and prognostic value within certain ethnic subgroups. We recently found that AA TNBC patients were ~3 times as likely as EA TNBC patients to have high nuclear levels of HSET, a centrosome-clustering kinesin. We found that higher nuclear HSET levels were also associated with more aggressive tumor features and decreased metastasis-free survival. As a result, nuclear HSET may be a racial disparity biomarker in TNBC. Furthermore, HSET may be a valuable target to suppress metastasis because we found that TNBC cell migration was inhibited by HSET knockdown. Overexpression of Npap60L, a nucleoporin isoform, is known to suppress nuclear import. In a search of publically-available gene expression databases, we found that AA TNBCs have lower Npap60L levels than EA TNBCs. Therefore, we hypothesize that low Npap60L levels in AA TNBCs promotes nuclear accumulation of HSET. Our novel paradigm that ethnic differences in nuclear transport pathways promote different subcellular localization of HSET, a key mediator of metastasis, is a groundbreaking conceptual advancement. It holds translational promise not only in metastatic risk prediction but also in providing an anti- metastatic therapeutic target for TNBC patients with high nuclear HSET. AIM 1 will establish nuclear HSET as a racial disparity biomarker by evaluating its nuclear expression as a predictor of a) metastasis, b) poor progression-free survival, and c) poor overall survival in AA TNBC patients. AIM 2 will test whether racial differences in the levels of a nucleoporin protein (Npap60L) involved in nuclear import promotes nuclear retention of HSET in AA TNBCs. The overall impact of this project will be to validate HSET as a racial disparity biomarker and mechanistically define the Npap60L-HSET axis as a new pathway that can be targeted to thwart metastatic onset in AA TNBC patients and alleviate ethnic breast cancer-related health disparity.
Public Health Relevance Statement: Public Health Relevance: Critical barriers to progress in treating triple negative breast cancer (TNBC), a particularly aggressive breast cancer subtype that is 2-3 times more common in African American (AA) than European American women, is a lack of reliable risk-predictive biomarkers and targeted therapies for TNBC. The goal of this project is (i) to validate nuclear HSET as a novel racial disparity biomarker that predicts poor clinical outcomes for TNBC, and (ii) to understand why AA TNBC cells accumulate more HSET in their nuclei. Successful outcomes of this STTR proposal may lead to the development of a clinically-facile immunohistochemistry kit that would enable identification of TNBC patients with high risk of progressing rapidly to metastatic disease.
Project Terms: Accounting; Adverse effects; African American; American; Attention; base; Binding (Molecular Function); Biological Assay; Biological Markers; Breast Cancer Cell; Breast Cancer cell line; Breast Cancer Patient; Breast Cancer Treatment; cancer cell; cancer type; cell motility; Cell Nucleus; Cell Survival; Centrosome; Clinical; clinical efficacy; cohort; combat; Confocal Microscopy; Cytotoxic Chemotherapy; Data; Databases; Development; Disease; early onset; ethnic difference; European; Evaluation; Formalin; Gene Expression; Gene Expression Profile; Goals; health disparity; high risk; Hormone Receptor; Human; Immunohistochemistry; Importins; improved; inhibitor/antagonist; Kinesin; Lead; malignant breast neoplasm; Malignant Neoplasms; matrigel; Mediator of activation protein; Metastatic to; Methods; Minority; Molecular; Mortality Vital Statistics; Neoplasm Metastasis; novel; Nuclear; Nuclear Import; Nuclear Localization Signal; Nuclear Pore Complex Proteins; nucleocytoplasmic transport; Outcome; overexpression; Paraffin Embedding; Pathway interactions; Patients; Pharmacologic Substance; Pilot Projects; Predictive Value; prognostic; prognostic value; Progression-Free Survivals; Protein Isoforms; Proteins; public health relevance; Race; racial difference; racial disparity; receptor; Recurrence; Relative (related person); Risk; Risk Marker; RNA; Running; Sampling; Small Business Technology Transfer Research; Solutions; Somatic Cell; Staining method; Stains; Statistical Methods; Subgroup; targeted treatment; Testing; Therapeutic; therapeutic target; Time; Tissue Microarray; Tissues; triple-negative invasive breast carcinoma; tumor; Tumor Biology; Validation; Woman
