Nek2 and Plk4: prognostic markers, drivers of breast tumorigenesis and drug resistance

Abstract

The Nek2 and Plk4 kinases serve as crucial regulators of mitotic processes such as the centrosome duplication cycle and spindle assembly. Deregulation of these processes can trigger chromosome instability and aneuploidy, which are hallmarks of many solid tumors, including breast cancer. Emerging data from the literature illustrated various functions of Nek2 in breast cancer models, with compelling evidence of its prognostic value in breast tumors. The two kinases control distinct steps in the centrosome-centriole cycle and their dysregulation lead to centrosome amplification, marked by the presence of more than two centrosomes within the cell. We found single or composite overexpression of these kinases in breast tumor samples, regardless of subtype, which strongly associated with poor prognosis. Interestingly, in a panel of established cell lines, both kinases are highly expressed in Her2-positive breast cancer cells exhibiting centrosome amplification and trastuzumab resistance. In summary, it appears that Nek2 and Plk4 might synergize to promote breast tumorigenesis and may also be involved in tamoxifen and trastuzumab resistance.

E2F Activators Signal and Maintain Centrosome Amplification in Breast Cancer Cells

“…Even though our results indicate that centrosome amplification is a redundant function of the E2F activators, our findings are relevant to the understanding of breast carcinogenesis, since E2F1, E2F3, and Nek2 are frequently overexpressed in breast tumors (26,97) and negatively impact the outcomes of survival (16,56,98). In fact, interference with Nek2 overexpression suppresses tumorigenesis of breast cancer cells (99).…”

“…Using data presented in Fig. 1a Ϫ (MCF7 and T47D), and triple-negative (MDA-MB-231 and MDA-MB-468) cell lines do not display centrosome amplification (56,62). MCF10A cells are used as a control, since they are nontransformed, immortalized human mammary epithelial cells that lack the p16 INK4A and p14 INK4B tumor suppressors and display normal p53 activity (66,67).…”

“…We have reported that MCF10A cells have a low percentage of centrosome amplification (56,62,69). To address whether the overexpression of E2F1, E2F2, or E2F3 is sufficient to induce centrosome amplification in MCF10A cells, we developed stable populations of MCF10A cells overexpressing E2F1, E2F2, or E2F3a.…”

“…Identifying the roles/ functions and sources of centrosomal/mitotic kinases in signaling centrosome amplification is important to breast cancer control, since the overexpression of 16 centrosomal/mitotic kinases in breast cancer, including Nek2 and Plk4, represents a molecular signature that strongly associates with poorly prognostic breast cancers (55). In fact, Nek2 and Plk4 are overexpressed in low-prognosis breast cancer molecular subtypes, individually associating with accelerated time-to-metastasis and time-to-relapse of breast cancer patients (56). Major unanswered questions regarding the role of the E2Fs in centrosome amplification are addressed in the present study, and we provide direct evidence that the E2F activators induce and maintain centrosome amplification in breast cancer cells and that Nek2 drives centrosome amplification downstream of the E2F3 activator.…”

Autoinhibition and relief mechanism for Polo-like kinase 4

“…All four members (Plk1-4) of this serine/threonine protein kinase family share sequence similarity and domain structure with the founding member, Drosophila Polo kinase (the homolog of human Plk1) (4). Plks are highly expressed in proliferating cells and are overexpressed in a variety of cancers where they have the potential to promote chromosomal instability and tumorigenesis (5)(6)(7)(8)(9). Previous studies have shown that Plk kinase activity can be limited to brief periods within the cell cycle through mechanisms involving the transcription, localization, degradation, and autoinhibition of the kinase (3,(10)(11)(12)(13).…”