MIZ1 Activation in Triple-negative Breast Cancer Racial Disparities

Triple-negative breast cancer (TNBC) is an aggressive and molecularly heterogeneous subtype of breast cancer that frequently exhibits resistance to chemotherapy leading to poorer clinical outcomes. African American (AA) women in the United States not only suffer from higher incidence rates of TNBC as compared to their European

American (EA) counterparts, but they also endure poorer survival outcomes. Racial disparities in TNBC outcomes are multifactorial and not fully explained by treatment variations and socioeconomical inequalities. As such, investigations into how the pathophysiology of TNBC differs between AA and EA women may offer new

insights into the manner through which biologic and socio-demographic factors converge in creating outcome disparities in TNBC. By sequencing the transcriptomes of primary TNBC tumors obtained from 3 independent patient cohorts, we detected aberrant activation of MIZ1 in ~70% of AA tumors, an event that was strongly

associated with poorer overall survival solely in AA patients. Based on these and other compelling findings, we hypothesize that (i) MIZ1 activation underlies disparate outcomes and poor overall survival rates of AA women, and (ii) targeting mechanistic vulnerabilities in MIZ1 signaling will provide for novel therapeutic approaches to

significantly improve AA TNBC outcomes. To test this hypothesis and to elucidate the molecular mechanisms whereby MIZ1 governs TNBC aggressiveness in AA patients, we endeavor to perform the following Specific Aims: (1) determine the mechanisms whereby MIZ1 drives AA tumorigenicity; (2) determine the mechanisms

whereby MIZ1 impacts cellular heterogeneity and macrophage polarization of AA TNBC tumors; and (3) determine the association of African ancestry with MIZ1 activation in AA TNBC and define the role of this event in TNBC progression. This project marks the first effort to harness mechanistic vulnerabilities in MIZ1 activation

and function to improve clinical outcomes of AA TNBC patients. Collectively, our innovative concept is highly impactful and could potentially redefine the clinical practice of treating AA TNBC patients, doing so by developing novel biomarkers, new drugs, and drug targets to improve clinical outcomes of AA TNBC patients.