title: 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.affiliation: Oncology Chemistry.
authors.forename: Pei-Pei
authors.initials: PP
authors.lastname: Kung
authors.affiliation: Oncology Research Unit.
authors.forename: Ricardo
authors.initials: R
authors.lastname: Martinez
authors.affiliation: Oncology Research Unit.
authors.forename: Zhou
authors.initials: Z
authors.lastname: Zhu
authors.affiliation: Pharmacokinetics, Dynamics and Metabolism, and.
authors.forename: Michael
authors.initials: M
authors.lastname: Zager
authors.affiliation: Oncology Research Unit.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Blasina
authors.affiliation: Oncology Research Unit.
authors.forename: Isha
authors.initials: I
authors.lastname: Rymer
authors.affiliation: Oncology Research Unit.
authors.forename: Jill
authors.initials: J
authors.lastname: Hallin
authors.affiliation: Oncology Research Unit.
authors.forename: Meirong
authors.initials: M
authors.lastname: Xu
authors.affiliation: Oncology Research Unit.
authors.forename: Christopher
authors.initials: C
authors.lastname: Carroll
authors.affiliation: Oncology Research Unit.
authors.forename: John
authors.initials: J
authors.lastname: Chionis
authors.affiliation: Oncology Research Unit.
authors.forename: Peter
authors.initials: P
authors.lastname: Wells
authors.affiliation: Pharmacokinetics, Dynamics and Metabolism, and.
authors.forename: Kirk
authors.initials: K
authors.lastname: Kozminski
authors.affiliation: Oncology Research Unit.
authors.forename: Jeffery
authors.initials: J
authors.lastname: Fan
authors.affiliation: Oncology Research Unit.
authors.forename: Oivin
authors.initials: O
authors.lastname: Guicherit
authors.affiliation: Oncology Chemistry.
authors.forename: Buwen
authors.initials: B
authors.lastname: Huang
authors.affiliation: Oncology Research Unit.
authors.forename: Mei
authors.initials: M
authors.lastname: Cui
authors.affiliation: Oncology Research Unit.
authors.forename: Chaoting
authors.initials: C
authors.lastname: Liu
authors.affiliation: Oncology Research Unit.
authors.forename: Zhongdong
authors.initials: Z
authors.lastname: Huang
authors.affiliation: Pharmaceuticals Science, Pfizer Worldwide Research and Development, La Jolla Laboratories, San Diego, California.
authors.forename: Anand
authors.initials: A
authors.lastname: Sistla
authors.affiliation: Oncology Research Unit.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Yang
authors.affiliation: Oncology Research Unit, brion.murray@pfizer.com.
authors.forename: Brion W
authors.initials: BW
authors.lastname: Murray
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001549:Benzamides / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics* / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D005998:Glycine / Q000031:analogs & derivatives* / Q000494:pharmacology; D006801:Humans; D053208:Kaplan-Meier Estimate; D016513:Mice, SCID; D018295:Neoplasms, Basal Cell / Q000188:drug therapy / Q000378:metabolism* / Q000401:mortality; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000401:mortality; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D002868:Chromosomal Proteins, Non-Histone; C000597118:PF-2771; C068688:centromere protein E; D005998:Glycine