Differential expression of kinesin family member 2C in triple negative breast cancer.

Women diagnosed with triple negative breast cancer can benefit neither from endocrine therapy nor from HER2-targeted therapies (1). We mined published microarray datasets (2, 3) to determine in an unbiased fashion and at the systems level genes most differentially expressed in the primary tumors of patients with breast cancer. We report here significant differential expression of the gene encoding kinesin family member 2C, KIF2C, when comparing the tumor cells of patients with triple negative breast cancer to normal mammary ductal cells (2). KIF2C was also differentially expressed in bulk tumor in human breast cancer (3). KIF2C mRNA was present at significantly increased quantities in TNBC tumor cells relative to normal mammary ductal cells. Analysis of human survival data revealed that expression of KIF2C in primary tumors of the breast was correlated with overall survival in patients with basal-like type cancer, while within triple negative breast cancer, primary tumor expression of KIF2C was correlated with overall survival in patients with mesenchymal and luminal androgen receptor subtype disease. KIF2C may be of relevance to initiation, maintenance or progression of triple negative breast cancers.

Differential expression of kinesin family member 23 in triple negative breast cancer.

Women diagnosed with triple negative breast cancer are predicted to benefit neither from endocrine therapy nor from HER2-targeted therapies (1). We mined published microarray datasets (2, 3) to determine in an unbiased fashion and at the systems level genes most differentially expressed in the primary tumors of patients with breast cancer. We report here significant differential expression of the gene encoding kinesin family member 23, KIF23, when comparing the tumor cells of patients with triple negative breast cancer to normal mammary ductal cells (2). KIF23 was also differentially expressed in bulk tumor in human breast cancer (3). KIF23 mRNA was present at significantly increased quantities in TNBC tumor cells relative to normal mammary ductal cells. Analysis of human survival data revealed that expression of KIF23 in primary tumors of the breast was correlated with recurrence-free survival in patients with luminal A and luminal B type cancer, while within triple negative breast cancer, primary tumor expression of KIF23 was correlated with recurrence-free survival in patients with basal-like 1 subtype disease. KIF23 may be of relevance to initiation, maintenance or progression of triple negative breast cancers.

Kinesin Family Member C1 (KIFC1/HSET): A Potential Actionable Biomarker of Early Stage Breast Tumorigenesis and Progression of High-Risk Lesions

The enigma of why some premalignant or pre-invasive breast lesions transform and progress while others do not remains poorly understood. Currently, no radiologic or molecular biomarkers exist in the clinic that can successfully risk-stratify high-risk lesions for malignant transformation or tumor progression as well as serve as a minimally cytotoxic actionable target for at-risk subpopulations. Breast carcinogenesis involves a series of key molecular deregulatory events that prompt normal cells to bypass tumor-suppressive senescence barriers. Kinesin family member C1 (KIFC1/HSET), which confers survival of cancer cells burdened with extra centrosomes, has been observed in premalignant and pre-invasive lesions, and its expression has been shown to correlate with increasing neoplastic progression. Additionally, KIFC1 has been associated with aggressive breast tumor molecular subtypes, such as basal-like and triple-negative breast cancers. However, the role of KIFC1 in malignant transformation and its potential as a predictive biomarker of neoplastic progression remain elusive. Herein, we review compelling evidence suggesting the involvement of KIFC1 in enabling pre-neoplastic cells to bypass senescence barriers necessary to become immortalized and malignant. We also discuss evidence inferring that KIFC1 levels may be higher in premalignant lesions with a greater inclination to transform and acquire aggressive tumor intrinsic subtypes. Collectively, this evidence provides a strong impetus for further investigation into KIFC1 as a potential risk-stratifying biomarker and minimally cytotoxic actionable target for high-risk patient subpopulations.

Differential expression of kinesin family member 20A in triple negative breast cancer.

Women diagnosed with triple negative breast cancer can benefit neither from endocrine therapy nor from HER2-targeted therapies (1). We mined published microarray datasets (2, 3) to determine in an unbiased fashion and at the systems level genes most differentially expressed in the primary tumors of patients with breast cancer. We report here significant differential expression of the gene encoding kinesin family member 20A, KIF20A, when comparing the tumor cells of patients with triple negative breast cancer to normal mammary ductal cells (2). KIF20A was also differentially expressed in bulk tumor in human breast cancer (3). KIF20A mRNA was present at significantly increased quantities in TNBC tumor cells relative to normal mammary ductal cells. Analysis of human survival data revealed that expression of KIF20A in primary tumors of the breast was correlated with distant metastasis-free survival in patients with luminal B type cancer in patients with HER2+ cancer, and in patients with normal-like cancer, while within triple negative breast cancer, primary tumor expression of KIF20A was correlated with distant metastasis-free survival in patients with basal-like 2 subtype disease. KIF20A may be of relevance to initiation, maintenance or progression of triple negative breast cancers.

In vivo proximity biotin ligation identifies the interactome of Egalitarian, a Dynein cargo adaptor

ABSTRACT Numerous motors of the Kinesin family contribute to plus-end-directed microtubule transport. However, almost all transport towards the minus-end of microtubules involves Dynein. Understanding the mechanism by which Dynein transports this vast diversity of cargo is the focus of intense research. In selected cases, adaptors that link a particular cargo with Dynein have been identified. However, the sheer diversity of cargo suggests that additional adaptors must exist. We used the Drosophila egg chamber as a model to address this issue. Within egg chambers, Egalitarian is required for linking mRNA with Dynein. However, in the absence of Egalitarian, Dynein transport into the oocyte is severely compromised. This suggests that additional cargoes might be linked to Dynein in an Egalitarian-dependent manner. We therefore used proximity biotin ligation to define the interactome of Egalitarian. This approach yielded several novel interacting partners, including P body components and proteins that associate with Dynein in mammalian cells. We also devised and validated a nanobody-based proximity biotinylation strategy that can be used to define the interactome of any GFP-tagged protein.

Screening and predicted value of potential biomarkers for breast cancer using bioinformatics analysis

Breast cancer is the most common cancer and the leading cause of cancer-related deaths in women. Increasing molecular targets have been discovered for breast cancer prognosis and therapy. However, there is still an urgent need to identify new biomarkers. Therefore, we evaluated biomarkers that may aid the diagnosis and treatment of breast cancer. We searched three mRNA microarray datasets (GSE134359, GSE31448 and GSE42568) and identified differentially expressed genes (DEGs) by comparing tumor and non-tumor tissues using GEO2R. Functional and pathway enrichment analyses of the DEGs were performed using the DAVID database. The protein–protein interaction (PPI) network was plotted with STRING and visualized using Cytoscape. Module analysis of the PPI network was done using MCODE. The associations between the identified genes and overall survival (OS) were analyzed using an online Kaplan–Meier tool. The redundancy analysis was conducted by DepMap. Finally, we verified the screened HUB gene at the protein level. A total of 268 DEGs were identified, which were mostly enriched in cell division, cell proliferation, and signal transduction. The PPI network comprised 236 nodes and 2132 edges. Two significant modules were identified in the PPI network. Elevated expression of the genes Discs large-associated protein 5 (DLGAP5), aurora kinase A (AURKA), ubiquitin-conjugating enzyme E2 C (UBE2C), ribonucleotide reductase regulatory subunit M2(RRM2), kinesin family member 23(KIF23), kinesin family member 11(KIF11), non-structural maintenance of chromosome condensin 1 complex subunit G (NCAPG), ZW10 interactor (ZWINT), and denticleless E3 ubiquitin protein ligase homolog(DTL) are associated with poor OS of breast cancer patients. The enriched functions and pathways included cell cycle, oocyte meiosis and the p53 signaling pathway. The DEGs in breast cancer have the potential to become useful targets for the diagnosis and treatment of breast cancer.

KIFC1 Is Associated with Basal Type, Cisplatin Resistance, PD-L1 Expression and Poor Prognosis in Bladder Cancer

Kinesin family member C1 (KIFC1), a minus end-directed motor protein, is reported to play an essential role in cancer. This study aimed to analyze KIFC1 expression and examine KIFC1 involvement in cisplatin resistance in bladder cancer (BC). Immunohistochemistry showed that 37 of 78 (47.4%) BC cases were positive for KIFC1. KIFC1-positive cases were associated with high T stage and lymph node metastasis. Kaplan-Meier analysis showed that KIFC1-positive cases were associated with poor prognosis, consistent with the results from public databases. Molecular classification in several public databases indicated that KIFC1 expression was increased in basal type BC. Immunohistochemistry showed that KIFC1-positive cases were associated with basal markers 34βE12, CK5 and CD44. KIFC1 expression was increased in altered TP53 compared to that in wild-type TP53. Immunohistochemistry showed that KIFC1-positive cases were associated with p53-positive cases. P53 knockout by CRISPR-Cas9 induced KIFC1 expression in BC cell lines. Knockdown of KIFC1 by siRNA increased the sensitivity to cisplatin in BC cells. Kaplan-Meier analysis indicated that prognosis was poor among KIFC1-positive BC patients treated with cisplatin-based chemotherapy. Immunohistochemistry showed that KIFC1-positive cases were associated with PD-L1-positive cases. High KIFC1 expression was associated with a favorable prognosis in patients treated with atezolizumab from the IMvigor 210 study. These results suggest that KIFC1 might be a promising biomarker and therapeutic target in BC.