Dataset Information

Overexpression of Kinesin Associated Protein 3 (KIFAP3) in Breast Cancer.

ABSTRACT: 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 of genes upregulated at the mRNA level in breast cancer followed by curation of the published literature to identify those genes that were not tested for overexpression at the protein level. We identified Kinesin Associated Protein 3 (KIFAP3) as one such molecule for further validation at the protein level. Immunohistochemical labeling of KIFAP3 using breast cancer tissue microarrays revealed overexpression of KIFAP3 protein in 84% (240/285) of breast cancers indicating the utility of our integrated approach of combining computational analysis with experimental biology.

SUBMITTER: Telikicherla D

PROVIDER: S-EPMC4734396 | biostudies-literature | 2012 May

REPOSITORIES: biostudies-literature

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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]

PMID: 26843789

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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.

Dataset Information

Overexpression of Kinesin Associated Protein 3 (KIFAP3) in Breast Cancer.

Publications

Overexpression of Kinesin Associated Protein 3 (KIFAP3) in Breast Cancer.

Similar Datasets

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