Abstract C29: Addressing how the Nek2 mitotic kinase facilitates the epithelial to mesenchymal transition in breast cancer

Abstract

Abstract Hispanics- (HAs) and African- Americans (AAs) are at higher risk of breast cancer (BC)-related death relative to European-Americans (EAs). Poor survival associates with socioeconomic status, genetics, and higher likelihood of developing hormone receptor-negative (ER-PR-, or HR-) BCs relative to EAs. Thus, it is imperative to find novel strategies to curb progression of these highly-malignant tumors. We propose that the accumulation of high frequencies of chromosome instability (CIN) is a risk factor for BC-related deaths in AA and HAs, since HR- BCs accumulate more CIN than other subtypes. The presence of CA/CIN in pre-malignant breast lesions and in most breast cancers (BCs), and their association with metastasis strongly suggest that CA/CIN are major drivers of multistage breast tumorigenesis. However, the direct involvement of CA/CIN in BCs has to be tested experimentally. TCGA analyses of BCs show that approximately 50% BCs are tetraploid; thus, it is highly significant to investigate whether, how and when CA/CIN contributes to mammary tumorigenesis. Our laboratory studies how unregulated centrosome and mitotic kinases drive CA/CIN in mammary epithelial cells to initiate and sustain HR- BCs. We demonstrated that CA appears in pre-malignant epithelial lesions, and that CA correlated with shorter-times of onset and invasion. In fact, CA in Her2+HR- BC and in MCF10A cells expressing H-RasG12V or H-RasG12V and c-Myc is partly dependent on Nek2. Nek2 regulates centrosome separation, and the spindle assembly checkpoint. Nek2 is overexpressed in 12% BCs and unregulation correlates with relapse-free survival of all BCs, and all subtypes, including basal, Her2+, Luminal A and Luminal B BCs. We have published that overexpression of GFP-Nek2 enhances CA in Her2+HR- cells silenced for E2F3 and results in invasive protrusions, suggestive of involvement in EMT, invasion, and metastasis. To establish the role of CA in mammary tumorigenesis, we overexpressed GFP-Nek2 in MCF10A cells, which are non-transformed human mammary epithelial cells. Nek2 overexpression is sufficient to enhance CA and CIN in MCF10A cells, and increase N-cadherin and vimentin, suggestive of EMT. Overall, our published and preliminary data indicate that Nek2-driven CA influence breast tumorigenesis. Future experiments will test Nek2's role in initiating and sustaining mammary tumors and metastasis. Because inhibitors against Nek2 are available, it is feasible to understand how Nek2 drives mammary tumorigenesis. Citation Format: Yainyrette Rivera-Rivera, Mihaela Marina, Harold I. Saavedra. Addressing how the Nek2 mitotic kinase facilitates the epithelial to mesenchymal transition in breast cancer. [abstract]. In: Proceedings of the Ninth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2016 Sep 25-28; Fort Lauderdale, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2017;26(2 Suppl):Abstract nr C29.