Abstract A096: Oncogenic TRIM37 is a genetic determinant of racial disparity in TNBC patients

Triple negative breast cancer (TNBC) is an aggressive breast cancer subtype that disproportionately affects younger African American (AA) women. A 5-year survival rate for AA TNBC patients is only 14% compared to 36% of Caucasian patients, which is attributed to early relapse, and metastasis to lung, liver and brain. Although disparities in treatment, co-morbid disease, and access to health care contribute to poor prognosis in AA women, a race-specific genetic component to TNBC disparity cannot be ruled out. To this end, our comprehensive preliminary studies have discovered genetic variations in tripartite motif-containing protein 37 (TRIM37) protein that strongly correlates with TNBC disparity and aggressive metastatic phenotype. Originally, we discovered and characterized TRIM37 as a new breast cancer oncogene that catalyzes histone H2A ubiquitination, a repressive epigenetic modification (Bhatnagar et. al., Nature 2014). Our recent follow-up studies combined with analysis of ethnically diverse genotype-tissue expression, quantitative trait loci, and 1000 genome datasets have discovered single nucleotide polymorphism in TRIM37 that segregate racially. Critically, we have identified TRIM37 polymorphic variants that are predominant in AA women and strongly associate with high TRIM37 in breast tissue. Furthermore, our genetic and biochemical studies establish a strong correlation between TRIM37 expression, metastasis and poor overall-survival using murine TNBC models and TNBC patient tissue analysis. Our comparative mechanistic investigations provide compelling evidence that TRIM37 accelerates TNBC metastasis by enhancing resistance to chemotherapy and inhibiting anoikis pathway, preferentially in AA TNBC relative to non-African American (non-AA) TNBC cells. Therefore, we hypothesize that TRIM37 is a genetic determinant of a high predisposition to metastatic TNBC in AA women, and a strategic target for clinical intervention. Clinical data indicate that AA women have a higher rate of metastatic recurrences compared to non-AA patients. An aggressive clinical course and our preliminary findings strongly suggest that TRIM37 preferentially influences clinical outcome of TNBC in AA women and represents a novel therapeutic target. In this proposal, we will test a highly innovative TRIM37 targeting approach that makes use of cutting-edge antibody-nanoparticle conjugates and antisense oligonucleotide strategy. The overall objectives of this proposal are to demonstrate that TRIM37 is a genetic variant associated with a high risk of metastatic TNBC in AA women and generate proof-of-concept data to treat metastatic TNBC by inhibiting TRIM37 in vivo. Our high precision-targeted approach offers a promising path for selective and effective TNBC treatment. If successful, the described strategy also fits into a broader goal of effective and superior TNBC treatments, and therefore, the potential to generate and replicate additional therapies using other TNBC regulators is very high.

Citation Format: Rachisan Gabriel Djiake Tihagam. Oncogenic TRIM37 is a genetic determinant of racial disparity in TNBC patients [abstract]. In: Proceedings of the Twelfth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2019 Sep 20-23; San Francisco, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl_2):Abstract nr A096.