Chemogenetic evaluation of the mitotic kinesin CENP-E reveals a critical role in triple-negative breast cancer.

Abstract

Breast cancer patients with tumors lacking the three diagnostic markers (ER, PR, and HER2) are classified as triple-negative (primarily basal-like) and have poor prognosis because there is no disease-specific therapy available. To address this unmet medical need, gene expression analyses using more than a thousand breast cancer samples were conducted, which identified elevated centromere protein E (CENP-E) expression in the basal-a molecular subtype relative to other subtypes. CENP-E, a mitotic kinesin component of the spindle assembly checkpoint, is shown to be induced in basal-a tumor cell lines by the mitotic spindle inhibitor drug docetaxel. CENP-E knockdown by inducible shRNA reduces basal-a breast cancer cell viability. A potent, selective CENP-E inhibitor (PF-2771) was used to define the contribution of CENP-E motor function to basal-like breast cancer. Mechanistic evaluation of PF-2771 in basal-a tumor cells links CENP-E-dependent molecular events (e.g., phosphorylation of histone H3 Ser-10; phospho-HH3-Ser10) to functional outcomes (e.g., chromosomal congression defects). Across a diverse panel of breast cell lines, CENP-E inhibition by PF-2771 selectively inhibits proliferation of basal breast cancer cell lines relative to premalignant ones and its response correlates with the degree of chromosomal instability. Pharmacokinetic-pharmacodynamic efficacy analysis in a basal-a xenograft tumor model shows that PF-2771 exposure is well correlated with increased phospho-HH3-Ser10 levels and tumor growth regression. Complete tumor regression is observed in a patient-derived, basal-a breast cancer xenograft tumor model treated with PF-2771. Tumor regression is also observed with PF-2771 in a taxane-resistant basal-a model. Taken together, CENP-E may be an effective therapeutic target for patients with triple-negative/basal-a breast cancer.

• Authors: Pei-Pei Kung, Ricardo Martinez, Zhou Zhu, Michael Zager, Alessandra Blasina, Isha Rymer, Jill Hallin, Meirong Xu, Christopher Carroll, John Chionis, Peter Wells, Kirk Kozminski, Jeffery Fan, Oivin Guicherit, Buwen Huang, Mei Cui, Chaoting Liu, Zhongdong Huang, Anand Sistla, Jennifer Yang, Brion W Murray
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 13 Issue 8 Pg. 2104-15 (Aug 2014) ISSN: 1538-8514 [Electronic] United States
• PMID: 24928852 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2014 American Association for Cancer Research.

Chemical References

• Antineoplastic Agents
• Benzamides
• Chromosomal Proteins, Non-Histone
• PF-2771
• centromere protein E
• Glycine

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Benzamides (pharmacology)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• Chromosomal Proteins, Non-Histone (genetics, metabolism)
• Female
• Gene Expression
• Glycine (analogs & derivatives, pharmacology)
• Humans
• Kaplan-Meier Estimate
• Mice, SCID
• Neoplasms, Basal Cell (drug therapy, metabolism, mortality)
• Triple Negative Breast Neoplasms (drug therapy, metabolism, mortality)
• Xenograft Model Antitumor Assays