The BH3-only protein NOXA serves as an independent predictor of breast cancer patient survival and defines susceptibility to microtubule targeting agents
| Autor: | H Fiegl, Lourdes Rocamora-Reverte, Walther Parson, Claudia Soratroi, Gerlinde Karbon, Haschka, Hubert Hackl, Andreas Villunger |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Cancer Research
Paclitaxel Immunology Triple Negative Breast Neoplasms Microtubules Article chemistry.chemical_compound Cellular and Molecular Neuroscience Breast cancer Text mining Microtubule hemic and lymphatic diseases medicine Humans MCL1 RNA Messenger Mitosis Cancer QH573-671 business.industry Cell Biology Translational research medicine.disease Proto-Oncogene Proteins c-bcl-2 chemistry Cell culture Apoptosis Cancer research Neoplasm Recurrence Local Apoptosis Regulatory Proteins business Cytology |
| Zdroj: | Cell Death and Disease, Vol 12, Iss 12, Pp 1-11 (2021) Cell Death & Disease |
| ISSN: | 2041-4889 |
| Popis: | Breast cancer (BC) treatment frequently involves microtubule-targeting agents (MTAs), such as paclitaxel, that arrest cells in mitosis. Sensitivity to MTAs is defined by a subset of pro- and anti-apoptotic BCL2 family proteins controlling mitochondrial apoptosis. Here, we aimed to determine their prognostic value in primary tumour samples from 92 BC patients. Our analysis identified high NOXA/PMAIP mRNA expression levels as an independent prognostic marker for improved relapse-free survival (RFS) and overall survival (OS) in multivariate analysis in BC patients, independent of their molecular subtype. Analysis of available TCGA datasets of 1060 BC patients confirmed our results and added a clear predictive value of NOXA mRNA levels for patients who received MTA-based therapy. In this TCGA cohort, 122 patients received MTA-treatment and high NOXA mRNA levels correlated with their progression-free interval (PFI) and OS. Our follow-up analyses in a panel of BC cell lines of different molecular subtypes identified NOXA protein expression as a key determinant of paclitaxel sensitivity in triple-negative breast cancer (TNBC) cells. Moreover, we noted highest additive effects between paclitaxel and chemical inhibition of BCLX, but not BCL2 or MCL1, documenting dependence of TNBC cells on BCLX for survival and paclitaxel sensitivity, defined by NOXA expression levels. |
| Databáze: | OpenAIRE |
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