Abstract B116: Evaluating the ability of clinically approved chemotherapeutics to decrease race-associated breast cancer mortality disparities via targeting the tumor-promoting effect of Crystallin Beta B2 (2020)

Abstract In the United States, breast cancer (BC) remains the second leading cause of cancer death in women. The unequal burden in the mortality of BC in African American (AA) women compared to Caucasian American (CA) women goes without full explanation. When socioeconomic factors such as education and income are accounted for, this mortality disparity persists. Therefore, to acquire an understanding of how to end BC disparities, it is crucial to examine the underlying cellular and molecular mechanisms driving this disproportionate outcome. Studies on gene expression analyses have identified a particular gene, CRYβB2, with higher expression in AA breast tumors. Expression of CRYβB2 was also found to be increased in studies comparing AA and CA colorectal, renal, glioblastoma, and prostate cancers, and has been linked with decreased survival. Although the precise mechanisms of elevated CRYβB2 expression remain unknown, overexpression is significantly associated with BC tumor promotion. In view of this, we investigated the biological effects of CRYβB2 in basal-like, triple negative breast cancer (TNBC) cell lines. CRYβB2 expression was manipulated via CRIPSR/Cas9-mediated knockout and lentiviral overexpression systems. Our preliminary data show enhanced proliferation and invasion in 3D cultures with cells overexpressing CRYβB2 compared to controls, suggesting two mechanisms by which CRYβB2-overexpression may enhance tumor promotion and promote poor patient outcome. To identify drugs that may specifically target cells overexpressing CRYβB2, we subjected one of our CRYβB2 model systems (SUM159 cells overexpressing CRYβB2, with CRYβB2 knocked out, and the parental SUM159 cells with low CRYβB2 expression) to increasing doses of 125 clinically approved chemotherapeutics. High content live cell imaging was used to evaluate the effects of the drugs by measuring 3D spheroid BC cell growth, and IC50 were generated to determine whether cells with altered CRYβB2 expression were more or less sensitive to particular classes of drugs. Drugs identified with increased cytotoxicity to cells overexpressing CRYβB2 were confirmed using two additional TNBC models with altered CRYβB2 levels. Additional in vitro mechanistic studies evaluating the effect of the drugs on proliferation, cytotoxicity and invasion of CRYβB2-overexpressing were executed in 3D cultures with live cell imaging. Drugs that significantly affect the proliferation or invasion of CRYβB2-overexpressing cells will be evaluated in future studies for efficacy and toxicity in conjunction with other chemotherapeutics via in vivo AA-specific xenografts and PDX models. This information will be used to explore the potential use of these chemotherapeutics for neoadjuvant or adjuvant therapy in BC patients with tumors that overexpress CRYβB2. The identification of clinically approved drugs that inhibit CRYβB2 function may quickly be applied in the clinic to increase survival rates until more effective and less toxic, targeted-therapies are developed. Citation Format: Portia L. Andrews, Denise K. Reaves, Megan E. Martin, Michael Tarpley, Kevin P. Williams, Jodie M. Fleming. Evaluating the ability of clinically approved chemotherapeutics to decrease race-associated breast cancer mortality disparities via targeting the tumor-promoting effect of Crystallin Beta B2 [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 B116.