The microtubule as a breast cancer target

Higa, Gerald M.

doi:10.1007/s12282-010-0224-7

Cited by 16 publications

(15 citation statements)

References 122 publications

(118 reference statements)

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“…Recently, several epothilones have been developed, which bind a similar site on tubulin but differ from the taxanes in specific binding characteristics, potency, and cross-resistance (28)(29)(30). A number of microtubule-stabilizing drug regimens are under investigation for refractory metastatic disease (31,32).…”

Section: Discussionmentioning

confidence: 99%

TPI-287, a New Taxane Family Member, Reduces the Brain Metastatic Colonization of Breast Cancer Cells

Fitzgerald

Emerson

Qian

et al. 2012

Molecular Cancer Therapeutics

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Brain metastases of breast and other cancers remain resistant to chemotherapeutic regimens that are effective systemically, in part due to the blood-brain barrier. We report that TPI-287, a new microtubule-stabilizing agent, displays in vitro cytotoxic activity similar to taxanes and epothilones. Unlike the taxanes, TPI-287 is permeable through the blood-brain barrier. Brain-to-plasma ratios of TPI-287 after a single injection typically exceeded one and were as high as 63.8 in the rat and 14.1 in the mouse. A brain-tropic derivative of the MDA-MB-231 triple-negative breast cancer cell line, 231-BR, was used to test whether TPI-287 may be efficacious at preventing or treating brain metastases. TPI-287 had growth inhibitory effects comparable with paclitaxel when 231-BR tumor cells were injected into the mammary fat pad. Brain metastatic colonization was determined by intracardiac injection of 231-BR cells, with treatment beginning on day 3 to 4 postinjection, culminating in a histologic count of brain metastases in brains necropsied days 25 to 28 postinjection. In this assay, paclitaxel, ixabepilone, and nab paclitaxel did not have significant inhibitory activity. TPI-287 was ineffective in the same assay using a 6 mg/kg every week schedule; however an 18 mg/kg dose delivered on days 3, 7, and 11 significantly reduced the outgrowth of brain metastases (55% reduction, P ¼ 0.028) and reduced proliferation in brain metastases (16% reduction, P ¼ 0.008). When TPI-287 treatment was delayed until days 18, 22, and 26 postinjection, efficacy was reduced (17% reduction, not significant). These data suggest that TPI-287 may have efficacy when administered early in the course of the disease.

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Section: Discussionmentioning

confidence: 99%

TPI-287, a New Taxane Family Member, Reduces the Brain Metastatic Colonization of Breast Cancer Cells

Fitzgerald

Emerson

Qian

et al. 2012

Molecular Cancer Therapeutics

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“…This observation might also be related to the fact that in Luminal A BRCA cell line (MCF7), estradiol is a potent stimulator of RNA polymerase II transcription 20 . These four lncRNAs up-regulated in Luminal A tumors also regulate microtubule-based movement, a process that results in the movement of organelles through polymerization or depolymerization of microtubules, this process is also a promising target for breast anticancer drugs 21 . Another biological process enriched was ciliary docking and organization.…”

Section: Discussionmentioning

confidence: 99%

A lncRNA landscape in breast cancer reveals a potential role for AC009283.1 in proliferation and apoptosis in HER2-enriched subtype

Cedro‐Tanda

Ríos-Romero

Romero-Córdoba

et al. 2020

Sci Rep

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Breast cancer is the most commonly diagnosed neoplasm in women worldwide with a well-recognized heterogeneous pathology, classified into four molecular subtypes: Luminal A, Luminal B, HER2enriched and Basal-like, each one with different biological and clinical characteristics. Long noncoding RNAs (lncRNAs) represent 33% of the human transcriptome and play critical roles in breast carcinogenesis, but most of their functions are still unknown. Therefore, cancer research could benefit from continued exploration into the biology of lncRNAs in this neoplasm. We characterized lncRNA expression portraits in 74 breast tumors belonging to the four molecular subtypes using transcriptome microarrays. To infer the biological role of the deregulated lncRNAs in the molecular subtypes, we performed co-expression analysis of lncRNA-mRNA and gene ontology analysis. We identified 307 deregulated lncRNAs in tumor compared to normal tissue and 354 deregulated lncRNAs among the different molecular subtypes. Through co-expression analysis between lncRNAs and proteincoding genes, along with gene enrichment analysis, we inferred the potential function of the most deregulated lncRNAs in each molecular subtype, and independently validated our results taking advantage of TCGA data. Overexpression of the AC009283.1 was observed in the HER2-enriched subtype and it is localized in an amplification zone at chromosome 17q12, suggesting it to be a potential tumorigenic lncRNA. The functional role of lncRNA AC009283.1 was examined through loss of function assays in vitro and determining its impact on global gene expression. These studies revealed that AC009283.1 regulates genes involved in proliferation, cell cycle and apoptosis in a HER2 cellular model. We further confirmed these findings through ssGSEA and CEMITool analysis in an independent HER2-amplified breast cancer cohort. Our findings suggest a wide range of biological functions for lncRNAs in each breast cancer molecular subtype and provide a basis for their biological and functional study, as was conducted for AC009283.1, showing it to be a potential regulator of proliferation and apoptosis in the HER2-enriched subtype.

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“…The microtubule has a critical regulatory function that affects not only mitosis, but also cytoskeletal shape, cell motility, and intracellular protein and organelle transport 10. Microtubules are composed of α- and β-tubulin subunits, each consisting of approximately 450 amino acids with a molecular weight of 50,000 Da, and are compacted into very complex monomeric structures 11.…”

Section: Biology Of the Microtubulementioning

confidence: 99%

Microtubule-targeting agents in oncology and therapeutic potential in hepatocellular carcinoma

Loong¹,

Park²

2014

OTT

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Abstract:In mammalian cells, microtubules are present both in interphase and dividing cells. In the latter, microtubules forming the mitotic spindle are highly dynamic and exquisitely sensitive to therapeutic inhibitors. Developed to alter microtubule function, microtubule-binding agents have been proven to be highly active as an anticancer treatment. Significant development of microtubule-binding agents has taken place in recent years, with newer anti-tubulin agents now showing novel properties of enhanced tumor specificity, reduced neurotoxicity, and insensitivity to chemoresistance mechanisms. Hepatocellular carcinoma remains one of the most difficult cancers to treat, with chemotherapies being relatively ineffective. There is now evidence to suggest that microtubule-binding agents may be effective in the treatment of hepatocellular carcinoma, especially when used in combination with mammalian target of rapamycin inhibitors. Preclinical models have suggested that the latter may be able to overcome resistance to microtubule binding agents. In this review article, recent developments of novel microtubule binding agents and their relevance to the treatment of hepatocellular carcinoma will be discussed.

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The microtubule as a breast cancer target

Cited by 16 publications

References 122 publications

TPI-287, a New Taxane Family Member, Reduces the Brain Metastatic Colonization of Breast Cancer Cells

TPI-287, a New Taxane Family Member, Reduces the Brain Metastatic Colonization of Breast Cancer Cells

A lncRNA landscape in breast cancer reveals a potential role for AC009283.1 in proliferation and apoptosis in HER2-enriched subtype

Microtubule-targeting agents in oncology and therapeutic potential in hepatocellular carcinoma

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