Abstract B070: Mitotic kinases differentially phosphorylate survivin in African American TNBC: Clues for racial disparity
Authors: Joshi Shriya , Garlapati Chakravarthy , Cavalli Luciane , Krishnamurti Uma , Kapoor Shobhna , Aneja Ritu 
Published: September 2020

Abstract
Protein diversity arising from alternative mRNA splicing or post-translational modifications (PTM) such as phosphorylation, methylation etc. plays a vital role in the modulation of cellular functions. Mitotic kinases such as polo-like kinase 1 (PLK1) and aurora B (AURKB) are known to phosphorylate survivin, an inhibitor of apoptosis family member, to promote cell survival and proliferation. This triad is significantly overexpressed in triple negative breast cancer (TNBC), an aggressive breast cancer (BC) subtype, associated with high proliferative capacity, propensity for distant metastasis and chemotherapeutic resistance. TNBC disproportionately afflicts African-American (AA) women relative to European-American (EA) women. AAs demonstrate a much more aggressive disease course compared to EAs. Thus far, efforts to examine molecular underpinnings of racial disparity in TNBC have largely focused on differences in gene expression and epigenetic aspects. Herein, we demonstrate the role of survivin phosphorylation, an important PTM, in enhancing cell proliferation and reducing apoptosis in AA compared to EA TNBC cells. Using the TCGA breast cancer dataset, our in silico analysis of various mitotic kinases yielded a significantly higher gene expression of PLK1 (p=0.061) and AURKB (p=0.003) in AA (n=41) compared to EA TNBC (n=86) patients. Surprisingly, we found no race-related differences in survivin gene expression in this dataset (n=127, p=0.343). In addition, there was no statistical difference in protein levels of survivin in TNBC clinical samples (n=142, p=0.45) as measured immunohistochemically. These findings led us to rationalize that the differential activation of survivin in AA vs. EA TNBC cells is based on PTM, and not due to its differential gene/protein expression levels. We hypothesize that differential phosphorylation of survivin by mitotic kinases underlies enhanced proliferative and anti-apoptotic activity in AA relative to EA TNBC. Survivin phosphorylation at Ser-20 and Thr-117 is known to regulate the activity of the chromosome passenger complex facilitating mitosis and cell proliferation. Moreover, p-survivin Thr-117 inhibits X-linked inhibitor of apoptosis-Smac interaction, which in turn prevents caspase-9 activation, leading to anti-apoptosis. We observed an upregulation of phosphorylated substrates of PLK1 and AURKB viz. p-survivin Ser-20 & p-survivin Thr-117, respectively, in AA compared to EA TNBC cells. Survivin ablation significantly attentuated cell proliferation, cell cycle progression, and increased cell apoptosis in AA compared to EA TNBC cells. These data strongly support our premise that higher survivin phosphorylation confers enhanced proliferative capacity and anti-apoptosis in AA compared to EA TNBC cells, suggesting that modulating survivin PTM may be a viable therapeutic strategy for AA TNBC patients. Further studies intended to tease out the role of survivin phosphorylation in TNBC racial disparity are currently underway in our lab.
Citation Format: Shriya Joshi, Chakravarthy Garlapati, Luciane Cavalli, Uma Krishnamurti, Shobhna Kapoor, Ritu Aneja. Mitotic kinases differentially phosphorylate survivin in African American TNBC: Clues for racial disparity [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 B070.