Journal Article

Myeloid cell leukemia-1 is an important apoptotic survival factor in triple-negative breast cancer

Goodwin, C M, Fesik, S W, Rossanese, O W, Olejniczak, E T

2015

Overview

Breast cancer is the second-most frequently diagnosed malignancy in US women. The triple-negative breast cancer (TNBC) subtype, which lacks expression of the estrogen receptor, progesterone receptor and human epidermal growth factor receptor-2, afflicts 15% of patients and is refractory to current targeted therapies. Like many cancers, TNBC cells often deregulate programmed cell death by upregulating anti-apoptotic proteins of the B-cell CLL/lymphoma 2 (Bcl-2) family. One family member, myeloid cell leukemia-1 (Mcl-1), is commonly amplified in TNBC and correlates with a poor clinical prognosis. Here we show the effect of silencing Mcl-1 and Bcl-2-like protein 1 isoform 1 (Bcl-xL) expression on viability in a panel of seventeen TNBC cell lines. Cell death was observed in a subset upon Mcl-1 knockdown. In contrast, Bcl-xL knockdown only modestly reduced viability, indicating that Mcl-1 is a more important survival factor. However, dual silencing of both Mcl-1 and Bcl-xL reduced viability in most cell lines tested. These proliferation results were recapitulated by BH3 profiling experiments. Treatment with a Bcl-xL and Bcl-2 peptide had only a moderate effect on any of the TNBC cell lines, however, co-dosing an Mcl-1-selective peptide with a peptide that inhibits Bcl-xL and Bcl-2 was effective in each line tested. Similarly, the selective Bcl-xL inhibitor WEHI-539 was only weakly cytotoxic across the panel, but sensitization by Mcl-1 knockdown markedly improved its EC 50 . ABT-199, which selectively inhibits Bcl-2, did not synergize with Mcl-1 knockdown, indicating the relatively low importance of Bcl-2 in these lines. Mcl-1 sensitivity is not predicted by mRNA or protein levels of a single Bcl-2 family member, except for only a weak correlation for Bak and Bax protein expression. However, a more comprehensive index composed of Mcl-1, Bcl-xL, Bim, Bak and Noxa protein or mRNA expression correlates well with Mcl-1 sensitivity in TNBC and can also predict Mcl-1 dependency in non-small cell lung cancer cell lines.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 13/2 / 13/89 / 13/95 / 38/1 / 38/39 / 45/29 / 631/67/395 / 692/53/2423 / 82/80 / 96/106 / Apoptosis / Apoptosis - drug effects / Apoptosis Regulatory Proteins - genetics / Apoptosis Regulatory Proteins - metabolism / bcl-2 Homologous Antagonist-Killer Protein - genetics / bcl-2 Homologous Antagonist-Killer Protein - metabolism / bcl-2-Associated X Protein - genetics / bcl-2-Associated X Protein - metabolism / Bcl-2-Like Protein 11 / bcl-X Protein - antagonists & inhibitors / bcl-X Protein - genetics / bcl-X Protein - metabolism / Biochemistry / Biomedical and Life Sciences / Bridged Bicyclo Compounds, Heterocyclic - pharmacology / Cell Biology / Cell Cycle Analysis / Cell Line, Tumor / Cell Survival - drug effects / Female / Humans / Life Sciences / Membrane Proteins - genetics / Membrane Proteins - metabolism / Myeloid Cell Leukemia Sequence 1 Protein - antagonists & inhibitors / Myeloid Cell Leukemia Sequence 1 Protein - genetics / Myeloid Cell Leukemia Sequence 1 Protein - metabolism / Original Paper / Proto-Oncogene Proteins - genetics / Proto-Oncogene Proteins - metabolism / Proto-Oncogene Proteins c-bcl-2 - genetics / Proto-Oncogene Proteins c-bcl-2 - metabolism / RNA Interference / RNA, Small Interfering - metabolism / Stem Cells / Sulfonamides - pharmacology / Triple Negative Breast Neoplasms - metabolism / Triple Negative Breast Neoplasms - pathology