Functional transcriptomic annotation and protein–protein interaction network analysis identify NEK2, BIRC5, and TOP2A as potential targets in obese patients with luminal A breast cancer

Abstract

PurposeAlthough obesity is a risk factor for breast cancer, little effort has been made in the identification of druggable molecular alterations in obese–breast cancer patients. Tumors are controlled by their surrounding microenvironment, in which the adipose tissue is a main component. In this work, we intended to describe molecular alterations at a transcriptomic and protein–protein interaction (PPI) level between obese and non-obese patients.Methods and resultsGene expression data of 269 primary breast tumors were compared between normal-weight (BMI < 25, n = 130) and obese (IMC > 30, n = 139) patients. No significant differences were found for the global breast cancer population. However, within the luminal A subtype, upregulation of 81 genes was observed in the obese group (FC ≥ 1.4). Next, we explored the association of these genes with patient outcome, observing that 39 were linked with detrimental outcome. Their PPI map formed highly compact cluster and functional annotation analyses showed that cell cycle, cell proliferation, cell differentiation, and cellular response to extracellular stimuli were the more altered functions. Combined analyses of genes within the described functions are correlated with poor outcome. PPI network analyses for each function were to search for druggable opportunities. We identified 16 potentially druggable candidates. Among them, NEK2, BIRC5, and TOP2A were also found to be amplified in breast cancer, suggesting that they could act as strategic players in the obese-deregulated transcriptome.ConclusionIn summary, our in silico analysis describes molecular alterations of luminal A tumors and proposes a druggable PPI network in obese patients with potential for translation to the clinical practice.Electronic supplementary materialThe online version of this article (10.1007/s10549-017-4652-3) contains supplementary material, which is available to authorized users.

Checking NEKs: Overcoming a Bottleneck in Human Diseases

“…Furthermore, the overexpression of NEK2 is associated with obese patients with luminal A breast cancer [118]. In summary, NEK2 has the potential to be used in drug development and cancer therapy.…”

A single cell atlas of the healthy breast tissues reveal clinically relevant clusters of breast epithelial cells

“…Cluster 11 is enriched for the expression of proliferation-associated genes including MKI67, CDK1, and TK1, apoptosis regulators (BIRC5, DEPDC1). It co-expressed TOP2A, BIRC5 and NEK2, which form a functional protein-protein network in luminal A breast cancer (Nuncia-Cantarero et al, 2018). In our second set of analyses, we found this cluster to be enriched for APOBEC3B and its elevated expression is associated with higher mutation rate (Olson et al, 2018).…”

NIMA-Related Kinase 2 Overexpression is Associated with Poor Survival in Cancer Patients: A Systematic Review and Meta-Analysis

“…[32][33][34] Previous studies have demonstrated that elevation in NEK2 contributes to the regulation of centrosome separation and spindle formation, and to ensuring that the chromosome structure is more stable and complete. 35,36 In cancer-related studies, NEK2 was found to be up-regulated in various types of cancer tissues and cell lines, suggesting the involvement of NEK2 in tumorigenesis. NEK2 has also been shown to be involved in abnormal cell differentiation, tumor proliferation, drug resistance, and poor prognosis in several kinds of tumors.…”

“…7,8 Elevation in NEK2 level contributes to the formation of centrosomal abnormalities and monopolar spindles and promotes aneuploidy by disrupting the control of mitotic checkpoints. 9,10 An increasing number of studies have reported that expression of NEK2 is increased in cancer and that up-regulation of NEK2 is associated with tumor progression and poor prognosis in various types of cancer, including breast cancer, 11,12 colorectal cancer, 13,14 cervical cancer, 15 and cholangiocarcinoma. 16 Notably, the number of studies on NEK2 is still small and the role, or roles, of NEK2 in cancer remains unclear.…”