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.
Highlights
Breast cancer is a heterogeneous disease with different subgroups characterized by specific clinical outcomes and responses to therapy [1]
Polo-like kinase 1 (PLK1) is overexpressed in triple-negative breast cancer To discover potential therapeutic targets for the poor prognosis-associated Triple-negative breast cancers (TNBC), a gene expression profiling was carried out on a cohort of 130 breast cancers
Alternative treatments are needed to improve survival of these patients. We found that both PLK1 and PLK4 are overexpressed in TNBC, and may represent potential therapeutic targets
Summary
Breast cancer is a heterogeneous disease with different subgroups characterized by specific clinical outcomes and responses to therapy [1]. In contrast to HER2 and luminal carcinomas, which can be treated with targeted therapy such as anti-HER2 monoclonal antibodies or hormonal therapies, respectively, there is no available targeted therapy for patients with TNBC who are managed exclusively with conventional chemotherapy. They show high rates of objective initial response, the majority of patients do not display a complete response and have a poorer prognosis than those within other breast tumor subgroups due to high rates of recurrence [6]. Because of this unfavorable prognosis and the lack of targeted therapy, there is currently an intensive search for identifying therapeutic targets for TNBC [7]
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