Abstract 1461: Targeting mitotic kinases in breast cancers in Latinas

Abstract

Abstract African Americans and Latino women (Latinas) in the US have higher risks of developing molecular subtypes of breast cancer that associate with poor-prognosis, including hormone receptor-negative (HR-): triple-negative (ER-PR-Her2-), and Her2-positive breast cancer relative to whites. These women also present with higher-stage breast tumors relative to whites. We specifically study Puerto Rican women, a population in which breast cancers are the primary cause of cancer-related death, and who display a higher frequency of HR- breast tumors than other Latinas. We propose that chromosome instability (CIN) is a principal contributor to poor prognosis of breast cancers in African Americans and Latinas, since HR- breast cancers accumulate the highest CIN of all breast cancer subtypes. CIN in cancers correlates with poor clinical outcomes and centrosome amplification (CA) -defined as the presence of 3 or more centrosomes within a cell-, and defective mitosis are two principal drivers of CIN. Albeit CA correlates with invasion, metastasis, poor clinical outcomes, and HR- subtypes, molecular mechanisms responsible for CA in breast cancers are still unknown. We have identified MPS1 and NEK2 as centrosomes/mitotic kinases that drive CA/CIN in HR- breast cancer cells, and that can potentially be targeted to curb the malignant behavior of the most aggressive breast cancer subtypes affecting ethnic minorities. MPS1 and NEK2 are upregulated in HR- breast tumors and are co-overexpressed in several predictive signatures of poor prognosis subtypes and metastasis. Our preliminary data indicated that these kinases are overexpressed in over 60% breast cancers from Puerto Rican women and that they are exclusively co-upregulated in basal breast cancers. Our preliminary data also showed that these two mitotic kinases can significantly influence epithelial-to-mesenchymal transition (EMT) and invasion -activities never described for mitotic kinases. Also, although inactivating NEK2 suppresses S phase, inhibition of MPS1 reduces survival of breast cancer cells. Because inhibitors are available for MPS1 and NEK2, it would be feasible to target these kinases to combat metastatic HR- breast cancers. Our work will allow the identification of pathways influenced by mitotic regulators in breast cancer cells driving invasion and metastasis and will provide potential prognostic markers for high-risk breast tumors in various ethnic/racial groups, including African American and Latinas (including Puerto Rican women). Citation Format: Yainyrette Rivera-Rivera, Mihaela Marina, Jamie King, Miyoung Lee, Harold I. Saavedra. Targeting mitotic kinases in breast cancers in Latinas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1461.