Abstract
Breast cancer remains a prominent global disease affecting women worldwide despite the emergence of novel therapeutic regimens. Metastasis is responsible for most cancer-related deaths, and acquisition of a mesenchymal and migratory cancer cell phenotypes contributes to this devastating disease. The utilization of kinase targets in drug discovery have revolutionized the field of cancer research but despite impressive advancements in kinase-targeting drugs, a large portion of the human kinome remains understudied in cancer. NEK5, a member of the Never-in-mitosis kinase family, is an example of such an understudied kinase. Here, we characterized the function of NEK5 in breast cancer. Stably overexpressing NEK5 cell lines (MCF7) and shRNA knockdown cell lines (MDA-MB-231, TU-BcX-4IC) were utilized. Cell morphology changes were evaluated using immunofluorescence and quantification of cytoskeletal components. Cell proliferation was assessed by Ki-67 staining and transwell migration assays tested cell migration capabilities. In vivo experiments with murine models were necessary to demonstrate NEK5 function in breast cancer tumor growth and metastasis. NEK5 activation altered breast cancer cell morphology and promoted cell migration independent of effects on cell proliferation. NEK5 overexpression or knockdown does not alter tumor growth kinetics but promotes or suppresses metastatic potential in a cell type-specific manner, respectively. While NEK5 activity modulated cytoskeletal changes and cell motility, NEK5 activity affected cell seeding capabilities but not metastatic colonization or proliferation in vivo. Here we characterized NEK5 function in breast cancer systems and we implicate NEK5 in regulating specific steps of metastatic progression.
Highlights
Breast cancer remains a predominant malignancy worldwide
We provide further evidence that supports a potential role for NEK5 in driving breast cancer cell motility and we parse out specific processes in breast cancer biology that are regulated, or not regulated, by NEK5 activity
Every patient-derived xenograft (PDX) model utilized in this study represented patients with triple negative breast cancer (TNBC) tumors in the greater New Orleans area
Summary
Breast cancer remains a predominant malignancy worldwide. With profound advancements in breast cancer therapeutic management, mortality rates have decreased overall. Invasive breast cancer remains difficult to manage with current regimens; approximately 13% of women will be diagnosed with invasive breast cancer in their lifetime [1]. Lehmann et al introduced a new classification system for breast cancers based on gene expression profiling of the tumors: Basal-like 1, basal-like 2, luminal androgen receptor and mesenchymal [4, 5]. In addition to the complex and heterogenous nature of breast cancers, metastasis and tumor recurrence are obstacles in effectively treating breast cancer [9,10,11]. There is an urgent need to continue to characterize potential drivers of these processes to formulate effective targeted therapeutic regimens for breast cancer
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