Chemogenetic Evaluation of the Mitotic Kinesin CENP-E Reveals a Critical Role in Triple-Negative Breast Cancer

Abstract

Breast cancer patients with tumors lacking the three diagnostic markers (ER, PR, and HER2) are classified as triple-negative (primarily basal-like) and have poor prognosis because there is no disease-specific therapy available. To address this unmet medical need, gene expression analyses using more than a thousand breast cancer samples were conducted, which identified elevated centromere protein E (CENP-E) expression in the basal-a molecular subtype relative to other subtypes. CENP-E, a mitotic kinesin component of the spindle assembly checkpoint, is shown to be induced in basal-a tumor cell lines by the mitotic spindle inhibitor drug docetaxel. CENP-E knockdown by inducible shRNA reduces basal-a breast cancer cell viability. A potent, selective CENP-E inhibitor (PF-2771) was used to define the contribution of CENP-E motor function to basallike breast cancer. Mechanistic evaluation of PF-2771 in basal-a tumor cells links CENP-E-dependent molecular events (e.g., phosphorylation of histone H3 Ser-

Whole-Genome Resequencing of Holstein Bulls for Indel Discovery and Identification of Genes Associated with Milk Composition Traits in Dairy Cattle

“…CENPE with two exonic indels (exons 58 and 68) and seven intronic indels was a component of the kinetochore complex and part of the spindle assembly checkpoint those were responsible for maintain chromosome congression and mitotic checkpoint [43]. It was a candidate gene for triple-negative breast cancer, and played a crucial role in suppressing tumorigenesis [44] Depletion of CENPE resulted in promoting the Drosophila epithelial tissues overgrowth [45]. …”

Mechanisms of Chromosome Congression during Mitosis

“…CENP-E is upregulated in individuals with rheumatoid arthritis [422] and with breast cancer [423]. Moreover, CENP-E expression negatively correlated with disease-specific survival in patients with breast cancer [423]. In contrast, human hepatocellular carcinoma exhibits abnormally low levels of CENP-E [424].…”

“…Moreover, the sensitivity to this inhibitor correlates with the degree of CIN, suggesting that cancers with elevated CIN may benefit from CENP-E-targeted therapy [423]. Finally, inhibition of CENP-E motor function by PF-2771 resulted in tumor regression in a patient-derived basal-like breast cancer xenograft tumor model [423].…”

“…Moreover, the sensitivity to this inhibitor correlates with the degree of CIN, suggesting that cancers with elevated CIN may benefit from CENP-E-targeted therapy [423]. Finally, inhibition of CENP-E motor function by PF-2771 resulted in tumor regression in a patient-derived basal-like breast cancer xenograft tumor model [423]. More recently, a new inhibitor of CENP-E directly targeting its ATPase activity, known as compound A, was found to have anti-proliferative activity in multiple cancer cell lines and in a xenograft nude mouse model [386,458].…”

XAB2 functions in mitotic cell cycle progression via transcriptional regulation of CENPE

“…Mitosis dysregulation often causes genome instability or aneuploidy, leads to mitotic catastrophe and cell death, and is closely associated with cancers and many other diseases. Thus, targeting mitosis has been proposed as an attractive therapeutic strategy for cancer therapy, 45, 46 for example, CENPE inhibitor like GSK923295, 47 syntelin 48 or PF2721 49 is now considered to have antitumour activity. Therefore, it will be interesting to investigate whether XAB2 can serve as a new anti-mitotic target for cancer therapy.…”