Overexpression of Kinesin Associated Protein 3 (KIFAP3) in Breast Cancer.
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ABSTRACT:
SUBMITTER: Telikicherla D
PROVIDER: S-EPMC4734396 | biostudies-literature | 2012 May
REPOSITORIES: biostudies-literature
Publications
Overexpression of Kinesin Associated Protein 3 (KIFAP3) in Breast Cancer.
Telikicherla Deepthi D Maharudraiah Jagadeesha J Pawar Harsh H Marimuthu Arivusudar A Kashyap Manoj Kumar MK Ramachandra Y L YL Roa Juan Carlos JC Pandey Akhilesh A
Journal of proteomics & bioinformatics 20120528 5
Gene expression profiling studies on breast cancer have generated catalogs of differentially expressed genes. However, many of these genes have not been investigated for their expression at the protein level. It is possible to systematically evaluate such genes in a high-throughput fashion for their overexpression at the protein level using breast cancer tissue microarrays. Our strategy involved integration of information from publicly available repositories of gene expression to prepare a list ...[more]
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Project description:BackgroundKinesin superfamily (KIFs) has a long-reported significant influence on the initiation, development, and progress of breast cancer. However, the prognostic value of whole family members was poorly done. Our study intends to demonstrate the value of kinesin superfamily members as prognostic biomarkers as well as a therapeutic target of breast cancer.MethodsComprehensive bioinformatics analyses were done using data from TCGA, GEO, METABRIC, and GTEx. LASSO regression was done to select tumor-related members. Nomogram was constructed to predict the overall survival (OS) of breast cancer patients. Expression profiles were testified by quantitative RT-PCR and immunohistochemistry. Transcription factor, GO and KEGG enrichments were done to explore regulatory mechanism and functions.ResultsA total of 20 differentially expressed KIFs were identified between breast cancer and normal tissue with 4 (KIF17, KIF26A, KIF7, KIFC3) downregulated and 16 (KIF10, KIF11, KIF14, KIF15, KIF18A, KIF18B, KIF20A, KIF20B, KIF22, KIF23, KIF24, KIF26B, KIF2C, KIF3B, KIF4A, KIFC1) overexpressed. Among which, 11 overexpressed KIFs (KIF10, KIF11, KIF14, KIF15, KIF18A, KIF18B, KIF20A, KIF23, KIF2C, KIF4A, KIFC1) significantly correlated with worse OS, relapse-free survival (RFS) and distant metastasis-free survival (DMFS) of breast cancer. A 6-KIFs-based risk score (KIF10, KIF15, KIF18A, KIF18B, KIF20A, KIF4A) was generated by LASSO regression with a nomogram validated an accurate predictive efficacy. Both mRNA and protein expression of KIFs are experimentally demonstrated upregulated in breast cancer patients. Msh Homeobox 1 (MSX1) was identified as transcription factors of KIFs in breast cancer. GO and KEGG enrichments revealed functions and pathways affected in breast cancer.ConclusionOverexpression of tumor-related KIFs correlate with worse outcomes of breast cancer patients and can work as potential prognostic biomarkers.
| S-EPMC7161125 | biostudies-literature
Project description:Purpose: Breast cancer is a genetically heterogenous disease with subtypes differing in prognosis and chemosensitivity. The basal-like breast cancer (BLBC) molecular subtype is associated with poorer outcomes, but is more responsive to taxane-based chemotherapy. We evaluated the role of kinesins, motor proteins interacting with microtubules, in influencing taxane resistance. Experimental Design: Kinesin (KIF) expression was studied in one local dataset comprising all taxane resistant breast cancers in relation to taxane resistance. Data in the NCI-60 cell line dataset (GSE5846) nd the MDACC dataset (GSE20194) is separately detailed. Results: In the local dataset, the kinesin KIF26B is overexpressed in taxane-resistant residual breast cancers post-chemotherapy. Conclusions: We show that kinesin overexpression correlates with taxane resistance in BLBC cell lines and tissue. Our results suggest a potential approach to overcoming taxane resistance through concurrent or sequential use of kinesin inhibitors, highlighting the ATP-binding domain as a drug development target. Kinesin (KIF) expression was studied in one local dataset comprising all taxane resistant breast cancers in relation to taxane resistance. Data in the NCI-60 cell line dataset (GSE5846) and the MDACC dataset (GSE20194) is separately detailed.
2012-12-01 | E-GEOD-22796 | biostudies-arrayexpress
Project description:Purpose: Breast cancer is a genetically heterogenous disease with subtypes differing in prognosis and chemosensitivity. The basal-like breast cancer (BLBC) molecular subtype is associated with poorer outcomes, but is more responsive to taxane-based chemotherapy. We evaluated the role of kinesins, motor proteins interacting with microtubules, in influencing taxane resistance. Experimental Design: Kinesin (KIF) expression was studied in one local dataset comprising all taxane resistant breast cancers in relation to taxane resistance. Data in the NCI-60 cell line dataset (GSE5846) nd the MDACC dataset (GSE20194) is separately detailed. Results: In the local dataset, the kinesin KIF26B is overexpressed in taxane-resistant residual breast cancers post-chemotherapy. Conclusions: We show that kinesin overexpression correlates with taxane resistance in BLBC cell lines and tissue. Our results suggest a potential approach to overcoming taxane resistance through concurrent or sequential use of kinesin inhibitors, highlighting the ATP-binding domain as a drug development target.
2012-12-01 | GSE22796 | GEO
Project description:BackgroundInflammatory breast cancer (IBC) is the most aggressive form of locally-advanced breast cancer. Identification of new therapeutic targets is crucial. We previously reported MARCKS mRNA overexpression in IBC in the largest transcriptomics study reported to date. Here, we compared MARCKS protein expression in IBC and non-IBC samples, and searched for correlations between protein expression and clinicopathological features.ResultsTumor samples showed heterogeneity with respect to MARCKS staining: 18% were scored as MARCKS-positive (stained cells ≥ 1%) and 82% as MARCKS-negative. MARCKS expression was more frequent in IBC (36%) than in non-IBC (11%; p = 1.4E-09), independently from molecular subtypes and other clinicopathological variables. We found a positive correlation between protein and mRNA expression in the 148/502 samples previously analyzed for MARCKS mRNA expression. MARCKS protein expression was associated with other poor-prognosis features in the whole series of samples such as clinical axillary lymph node or metastatic extension, high pathological grade, ER-negativity, PR-negativity, HER2-positivity, and triple-negative and HER2+ statutes. In IBC, MARCKS expression was the sole tested variable associated with poor MFS.Materials and methodsWe retrospectively analyzed MARCKS protein expression by immunohistochemistry in 502 tumors, including 133 IBC and 369 non-IBC, from Tunisian and French patients. All samples were pre-therapeutic clinical samples. We searched for correlations between MARCKS expression and clinicopathological features including the IBC versus non-IBC phenotype and metastasis-free survival (MFS).ConclusionsMARCKS overexpression might in part explain the poor prognosis of IBC. As an oncogene associated with poor MFS, MARCKS might represent a new potential therapeutic target in IBC.
| S-EPMC5351628 | biostudies-literature
Project description:Purpose: Breast cancer is a genetically heterogenous disease with subtypes differing in prognosis and chemosensitivity. The basal-like breast cancer (BLBC) molecular subtype is associated with poorer outcomes, but is more responsive to taxane-based chemotherapy. We evaluated the role of kinesins, motor proteins interacting with microtubules, in influencing taxane resistance. Experimental Design: Kinesin (KIF) expression was studied in one local dataset comprising all taxane resistant breast cancers in relation to taxane resistance. Data in the NCI-60 cell line dataset (GSE5846) nd the MDACC dataset (GSE20194) is separately detailed. Results: In the local dataset, the kinesin KIF26B is overexpressed in taxane-resistant residual breast cancers post-chemotherapy. Conclusions: We show that kinesin overexpression correlates with taxane resistance in BLBC cell lines and tissue. Our results suggest a potential approach to overcoming taxane resistance through concurrent or sequential use of kinesin inhibitors, highlighting the ATP-binding domain as a drug development target. Kinesin (KIF) expression was studied in one local dataset comprising all taxane resistant breast cancers in relation to taxane resistance. Data in the NCI-60 cell line dataset (GSE5846) and the MDACC dataset (GSE20194) is separately detailed.
| S-ECPF-GEOD-22796 | biostudies-other
Project description:Breast cancer is a genetically heterogenous disease with subtypes differing in prognosis and chemosensitivity. The basal-like breast cancer (BLBC) molecular subtype is associated with poorer outcomes, but is more responsive to taxane-based chemotherapy. Kinesins are intracellular transport proteins that interact with microtubules, which are also the mechanistic target for taxanes. We investigated the relationship between taxane resistance in BLBC and kinesins using both expression and functional studies. Kinesin (KIF) expression was evaluated in three settings in relation to taxane resistance: (i) the NCI-60 cancer cell lines, (ii) pre-treatment samples from four BLBC patient cohorts receiving neoadjuvant chemotherapy regimens with and without taxanes, and (iii) post-treatment samples from residual breast cancer following neoadjuvant taxane-containing chemotherapy. We used a novel functional approach to gene modification, validation-based insertional mutagenesis, to select kinesin-overexpressing clones of BLBC cells for evaluation of related mechanisms of taxane resistance. In the NCI-60 cell line dataset, overexpression of the kinesin KIFC3 is significantly correlated with resistance to both docetaxel (P < 0.001) and paclitaxel (P < 0.001), but not to platinum-based chemotherapy, including carboplatin (P = 0.49) and cisplatin (P = 0.10). Overexpression of KIFC3 and KIF5A in pre-chemotherapy samples similarly predicted resistance to paclitaxel in the MDACC cohorts (P = 0.01); no KIF predicted resistance to fluorouracil-epirubicin-cyclophosphamide or cisplatin in BLBC patient cohorts treated without taxanes. KIF12 is the most overexpressed KIF gene in post-chemotherapy taxane-resistant residual breast cancers (2.8-fold-change). Functional studies established that overexpression of KIFC3, KIF5A, and KIF12 were specific in mediating resistance to docetaxel and not vincristine or doxorubicin. Mutation of the ATP-binding domain of a kinesin abolished its ability to mediate docetaxel resistance. Overall, kinesin overexpression correlates with specific taxane resistance in BLBC cell lines and tissues. Our results suggest a novel approach for drug development to overcome taxane resistance in breast cancer through concurrent or sequential use of kinesin inhibitors.
| S-EPMC4038085 | biostudies-literature
Project description:The molecular events that lead to malignant transformation and subsequent metastasis of breast carcinoma include alterations in the cells at genome, transcriptome and proteome levels. In this study, we used publicly available gene expression databases to identify those candidate genes which are upregulated at the mRNA level in breast cancers but have not been systematically validated at the protein level. Based on an extensive literature search, we identified ribosome binding protein 1 (RRBP1) as a candidate that is upregulated at the mRNA level in five different studies but its protein expression had not been investigated. Immunohistochemical labeling of breast cancer tissue microarrays was carried out to determine the expression of RRBP1 in a large panel of breast cancers. We found that RRBP1 was overexpressed in 84% (177/219) of breast carcinoma cases tested. The subcellular localization of RRBP1 was mainly observed to be in the cytoplasm with intense staining in the perinuclear region. Our findings suggest that RRBP1 is an interesting molecule that can be further studied for its potential to serve as a breast cancer biomarker. This study also demonstrates how the integration of biological data from available resources in conjunction with systematic evaluation approaches can be successfully applied to clinical proteomics.
| S-EPMC3439379 | biostudies-literature
Project description:Background:KIF20A plays an indispensable role in cytokinesis regulation, which is important for tumor proliferation and growth. Recently, the oncogenic role of KIF20A has been well documented in several cancers. However, its clinical role in epithelial ovarian cancer (EOC) remains not reported yet. We investigated its expression and its role in promoting invasion and chemoresistance in EOC cells. Patients and methods:KIF20A transcription and translation levels were investigated in normal ovarian epithelial cell, ovarian cancer cells, and 10 pairs of fresh EOC tissues and adjacent normal ovarian tissues by real-time quantitative polymerase chain reaction and Western blots. Moreover, KIF20A protein level was also examined by immunohistochemistry in 150 EOC tissues. The correlation between KIF20A expression and clinical variables was analyzed by statistical methods. We also used wound healing assay, transwell assay MTT, and Annexin V/PI to explore KIF20A functions. Results:KIF20A expression was obviously elevated at both mRNA and protein levels in EOC cell lines and clinical cancer tissues compared with normal ovarian epithelial cell and adjacent normal ovarian tissues. KIF20A protein expression was highly correlated with International Federation of Gynecology and Obstetrics stage (P=0.008), lymph node metastasis (P=0.002), intraperitoneal metastasis (P<0.001), vital status at last follow-up (P<0.001), intraperitoneal recurrence (P=0.030), tumor recurrence (P=0.005), drug resistance (P=0.013), and ascites with tumor cells (P<0.001). KIF20A overexpression was closely related to poorer overall survival and disease progression-free survival. Furthermore, Cox regression analysis revealed that KIF20A can act as an independent hazard indicator for predicting clinical outcomes in EOC patients. Interestingly, KIF20A overexpression promoted invasion and metastasis of EOC cells and also confers resistance to cisplatin. Conclusion:Our findings indicated that KIF20A overexpression predicts unfavorable clinical outcome, revealing that KIF20A holds a promising potential to serve as a useful prognostic biomarker for EOC patients.
| S-EPMC6140728 | biostudies-literature
Project description:Ispinesib (SB-715992) is a potent inhibitor of kinesin spindle protein, a kinesin motor protein essential for the formation of a bipolar mitotic spindle and cell cycle progression through mitosis. Clinical studies of ispinesib have shown a 9% response rate in patients with locally advanced or metastatic breast cancer and a favorable safety profile without significant neurotoxicities, gastrointestinal toxicities, or hair loss. To better understand the potential of ispinesib in the treatment of breast cancer, we explored the activity of ispinesib alone and in combination with several therapies approved for the treatment of breast cancer.We measured the ispinesib sensitivity and pharmacodynamic response of breast cancer cell lines representative of various subtypes in vitro and as xenografts in vivo and tested the ability of ispinesib to enhance the antitumor activity of approved therapies.In vitro, ispinesib displayed broad antiproliferative activity against a panel of 53 breast cell lines. In vivo, ispinesib produced regressions in each of five breast cancer models and tumor-free survivors in three of these models. The effects of ispinesib treatment on pharmacodynamic markers of mitosis and apoptosis were examined in vitro and in vivo, revealing a greater increase in both mitotic and apoptotic markers in the MDA-MB-468 model than in the less sensitive BT-474 model. In vivo, ispinesib enhanced the antitumor activity of trastuzumab, lapatinib, doxorubicin, and capecitabine and exhibited activity comparable with paclitaxel and ixabepilone.These findings support further clinical exploration of kinesin spindle protein inhibitors for the treatment of breast cancer.
| S-EPMC2844774 | biostudies-literature
Project description:BackgroundNUCKS (Nuclear, Casein Kinase and Cyclin-dependent Kinase Substrate) is a nuclear, DNA-binding and highly phosphorylated protein. A number of reports show that NUCKS is highly expressed on the level of mRNA in several human cancers, including breast cancer. In this work, NUCKS expression on both RNA and protein levels was studied in breast tissue biopsies consisted of invasive carcinomas, intraductal proliferative lesions, benign epithelial proliferations and fibroadenomas, as well as in primary cultures derived from the above biopsies. Specifically, in order to evaluate the level of NUCKS protein in correlation with the histopathological features of breast disease, immunohistochemistry was employed on paraffin sections of breast biopsies of the above types. In addition, NUCKS expression was studied by means of Reverse Transcription PCR (RT-PCR), real-time PCR (qRT-PCR) and Western immunoblot analyses in the primary cell cultures developed from the same biopsies.ResultsThe immunohistochemical Results showed intense NUCKS staining mostly in grade I and II breast carcinomas compared to normal tissues. Furthermore, NUCKS was moderate expressed in benign epithelial proliferations, such as adenosis and sclerosing adenosis, and highly expressed in intraductal lesions, specifically in ductal carcinomas in situ (DCIS). It is worth noting that all the fibroadenoma tissues examined were negative for NUCKS staining. RT-PCR and qRT-PCR showed an increase of NUCKS expression in cells derived from primary cultures of proliferative lesions and cancerous tissues compared to the ones derived from normal breast tissues and fibroadenomas. This increase was also confirmed by Western immunoblot analysis. Although NUCKS is a cell cycle related protein, its expression does not correlate with Ki67 expression, neither in tissue sections nor in primary cell cultures.ConclusionThe results show overexpression of the NUCKS protein in a number of non malignant breast lesions and cancerous tissues. In particular, the NUCKS overexpression in ADH and DCIS indicates a significant role of this protein in neoplastic progression.
| S-EPMC2743642 | biostudies-literature