Abstract B065: Polo-like kinase 1 (PLK1) and aurora kinase B (AURKB) collude with survivin to augment tumor cell proliferation in African-American TNBC: Implications for racial disparity

Abstract

Abstract Mitotic kinases such as polo-like kinase 1 (PLK1) and aurora kinase B (AURKB) are known to phosphorylate survivin, an IAP family member, to mediate cell survival and proliferation. Interestingly, the triad is significantly overexpressed in multiple tumors including triple-negative breast cancer (TNBC), an aggressive breast cancer subtype, associated with high proliferative capacity, propensity for distant metastasis and therapeutic resistance. Not only TNBCs disproportionately afflict African-American (AA) women compared to European-American (EA) women, AAs demonstrate a much more aggressive disease course compared to their EA counterparts. Largely, most efforts on examining molecular underpinnings of breast cancer-related racial disparity have so far focused on differences in gene expression, epigenetic aspects, and single-nucleotide polymorphisms (SNPs) in tumor tissues. Herein, employing racially distinct TNBC cells, we illuminate the role of survivin phosphorylation, an important post-translational modification, in dictating enhanced cell proliferation and survival in AA TNBC cells compared to EA TNBC cells. Using the publically-available TCGA dataset, our comprehensive in silico analysis of various mitotic and cyclin-dependent 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 TCGA breast dataset (n=127, p=0.343). In addition, there was no statistical difference in survivin protein levels as shown by immunohistochemical staining of survivin in TNBC samples (n=142, p=0.45) from Emory Hospital, Atlanta. Based on these intriguing findings, we hypothesized that the differential functional activity of survivin in AA vs EA TNBC cells augments tumor proliferation in AA TNBC cells. Literature suggests that phosphorylation of survivin at Ser-20 and Thr-117 plays a role in the activity of the chromosome passenger complex (CPC) facilitating mitosis and cell proliferation. We observed an upregulation of phosphorylated substrates of PLK1 and AURKB, namely, p-survivin [Ser-20] and p-survivin [Thr-117], respectively, in AA compared to EA TNBC cell lines. Since most proteins are regulated post-translationally to perform diverse activities, we next knocked down survivin expression in AA, and EA TNBC cell lines, using a siRNA approach. Survivin ablation significantly attenuated cell proliferation, cell cycle progression, but not invasion, and migration in AA TNBC cells compared to EA TNBC cells. These data strongly support our premise that higher functional activity of survivin confers enhanced proliferative capacity on AA TNBC cells compared to EA TNBC cells, suggesting that survivin may be a viable therapeutic target for AA TNBC patients. Further studies intended to tease out the role of survivin phosphorylation in TNBC-related racial disparity are currently under way in our lab. Citation Format: Chakravarthy Garlapati, Shriya Joshi, Rida Padmashree, Ritu Aneja. Polo-like kinase 1 (PLK1) and aurora kinase B (AURKB) collude with survivin to augment tumor cell proliferation in African-American TNBC: Implications for racial disparity [abstract]. In: Proceedings of the Eleventh AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2018 Nov 2-5; New Orleans, LA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl):Abstract nr B065.