A novel racial disparity marker for risk prediction in triple negative breast cancer patients

DESCRIPTION provided by applicant 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 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 Npap L 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 Npap L levels than EA TNBCs Therefore we hypothesize that low Npap L 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 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 will test whether racial differences in the levels of a nucleoporin protein Npap L 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 Npap L 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 Critical barriers to progress in treating triple negative breast cancer TNBC a particularly aggressive breast cancer subtype that is 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