title: Polo-like kinase 1: a potential therapeutic option in combination with conventional chemotherapy for the management of patients with triple-negative breast cancer.
abstract: Breast cancers are composed of molecularly distinct subtypes with different clinical outcomes and responses to therapy. To discover potential therapeutic targets for the poor prognosis-associated triple-negative breast cancer (TNBC), gene expression profiling was carried out on a cohort of 130 breast cancer samples. Polo-like kinase 1 (PLK1) was found to be significantly overexpressed in TNBC compared with the other breast cancer subtypes. High PLK1 expression was confirmed by reverse phase protein and tissue microarrays. In triple-negative cell lines, RNAi-mediated PLK1 depletion or inhibition of PLK1 activity with a small molecule (BI-2536) induced an increase in phosphorylated H2AX, G(2)-M arrest, and apoptosis. A soft-agar colony assay showed that PLK1 silencing impaired clonogenic potential of TNBC cell lines. When cells were grown in extracellular matrix gels (Matrigel), and exposed to BI-2536, apoptosis was observed specifically in TNBC cancerous cells, and not in a normal cell line. When administrated as a single agent, the PLK1 inhibitor significantly impaired tumor growth in vivo in two xenografts models established from biopsies of patients with TNBC. Most importantly, the administration of BI-2536, in combination with doxorubicin + cyclophosphamide chemotherapy, led to a faster complete response compared with the chemotherapy treatment alone and prevented relapse, which is the major risk associated with TNBC. Altogether, our observations suggest PLK1 inhibition as an attractive therapeutic approach, in association with conventional chemotherapy, for the management of patients with TNBC.
authors.affiliation: Institut Curie, Centre de Recherche, Paris, France.
authors.forename: Virginie
authors.initials: V
authors.lastname: Maire
authors.forename: Fariba
authors.initials: F
authors.lastname: Némati
authors.forename: Marion
authors.initials: M
authors.lastname: Richardson
authors.forename: Anne
authors.initials: A
authors.lastname: Vincent-Salomon
authors.forename: Bruno
authors.initials: B
authors.lastname: Tesson
authors.forename: Guillem
authors.initials: G
authors.lastname: Rigaill
authors.forename: Eléonore
authors.initials: E
authors.lastname: Gravier
authors.forename: Bérengère
authors.initials: B
authors.lastname: Marty-Prouvost
authors.forename: Leanne
authors.initials: L
authors.lastname: De Koning
authors.forename: Guillaume
authors.initials: G
authors.lastname: Lang
authors.forename: David
authors.initials: D
authors.lastname: Gentien
authors.forename: Aurélie
authors.initials: A
authors.lastname: Dumont
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Barillot
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Marangoni
authors.forename: Didier
authors.initials: D
authors.lastname: Decaudin
authors.forename: Sergio
authors.initials: S
authors.lastname: Roman-Roman
authors.forename: Alain
authors.initials: A
authors.lastname: Pierré
authors.forename: Francisco
authors.initials: F
authors.lastname: Cruzalegui
authors.forename: Stéphane
authors.initials: S
authors.lastname: Depil
authors.forename: Gordon C
authors.initials: GC
authors.lastname: Tucker
authors.forename: Thierry
authors.initials: T
authors.lastname: Dubois
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D051379:Mice; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011621:Pteridines / Q000494:pharmacology*; D015854:Up-Regulation; D023041:Xenograft Model Antitumor Assays; D000097869:Polo-Like Kinase 1
chemical_list: D018797:Cell Cycle Proteins; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D011621:Pteridines; D000097869:Polo-Like Kinase 1; C518477:BI 2536