title: Specific kinesin expression profiles associated with taxane resistance in basal-like breast cancer.
abstract: 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.
authors.affiliation: Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, 9500 Euclid Avenue (NE-50), Cleveland, OH 44195, USA.
authors.forename: Min Han
authors.initials: MH
authors.lastname: Tan
authors.forename: Sarmishtha
authors.initials: S
authors.lastname: De
authors.forename: Gurkan
authors.initials: G
authors.lastname: Bebek
authors.forename: Mohammed S
authors.initials: MS
authors.lastname: Orloff
authors.forename: Robert
authors.initials: R
authors.lastname: Wesolowski
authors.forename: Erinn
authors.initials: E
authors.lastname: Downs-Kelly
authors.forename: G Thomas
authors.initials: GT
authors.lastname: Budd
authors.forename: George R
authors.initials: GR
authors.lastname: Stark
authors.forename: Charis
authors.initials: C
authors.lastname: Eng
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000328:Adult; D000368:Aged; D018943:Anthracyclines / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics*; D001952:Bridged-Ring Compounds / Q000494:pharmacology* / Q000627:therapeutic use; D045744:Cell Line, Tumor; D016000:Cluster Analysis; D000077143:Docetaxel; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D015870:Gene Expression; D020869:Gene Expression Profiling; D057809:HEK293 Cells; D006801:Humans; D016547:Kinesins / Q000235:genetics* / Q000378:metabolism; D008875:Middle Aged; D009367:Neoplasm Staging; D017239:Paclitaxel / Q000494:pharmacology; D011485:Protein Binding; D043823:Taxoids / Q000494:pharmacology* / Q000627:therapeutic use; D014750:Vincristine / Q000494:pharmacology
chemical_list: D018943:Anthracyclines; D000970:Antineoplastic Agents; D001952:Bridged-Ring Compounds; D043823:Taxoids; D000077143:Docetaxel; C080625:taxane; D014750:Vincristine; D000255:Adenosine Triphosphate; D016547:Kinesins; D017239:Paclitaxel