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 þ 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. Cancer Res; 73(2); 813-23. Ó2012 AACR.

Impaired PRC2 activity promotes transcriptional instability and favors breast tumorigenesis

“…This further suggests that association of high EZH2 with cancer aggressiveness might reflect the increased cell proliferation occurring in advanced stages of prostate cancer (e.g., see Tomlins et al 2007). A similar analysis on a breast cancer cohort comprising 146 samples from the four main molecular subtypes (Maire et al 2013) confirmed that EZH2 expression correlates with proliferation markers (Supplemental Fig. S2B).…”

The Genomic Landscape of Pancreatic and Periampullary Adenocarcinoma

“…In addition, the prognostic relevance of genes like PIK3R1, NEK3, SASH1, and RASA3 on chromosome 17p13 was also defined for the intestinal subtype (9). The intestinal subtype specific aberration patterns including deletion of 5q, gain of 3q21-26 and overexpression of CCNL1 and KLF5 and downregulation of PLK2 and PPP3CA were also identified in other tumor types (29,(33)(34)(35). Furthermore, subtyping of periampullary adenocarcinomas using the PAM50 classifier identified a subgroup of pancreatobiliary tumors that are basal-like with worse prognosis as identified by Moffitt and colleagues as well; however, the Collisson's subtypes were not prognostically different in our cohort.…”

BI 6727 and GSK461364 suppress growth and radiosensitize osteosarcoma cells, but show limited cytotoxic effects when combined with conventional treatments

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