Journal
ONCOGENE
Volume 38, Issue 17, Pages 3261-3273Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41388-018-0635-z
Keywords
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Funding
- CIFRE grant (ANRT contract) [20150995]
- Ligue contre le cancer
- Odyssea
- Canceropole Grand Ouest (MATURE project 2017-18)
- ARC [R15083NN]
- ANR [15-CE18-0008]
- INCa
- DGOS (SIRIC ILIAD, INCa-DGOS Inserm) [12558]
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Selective inhibition of BCL-2 is expected to enhance therapeutic vulnerability in luminal estrogen receptor-positive breast cancers. We show here that the BCL-2 dependency of luminal tumor cells is nevertheless mitigated by breast cancer-associated fibroblasts (bCAFs) in a manner that defines MCL-1 as another critical therapeutic target. bCAFs favor MCL-1 expression and apoptotic resistance in luminal cancer cells in a IL-6 dependent manner while their own, robust, survival also relies on MCL-1. Studies based on ex vivo cultures of human luminal breast cancer tissues further argue that the contribution of stroma-derived signals to MCL-1 expression shapes BCL-2 dependency. Thus, MCL-1 inhibitors are beneficial for targeted apoptosis of breast tumor ecosystems, even in a subtype where MCL-1 dependency is not intrinsically driven by oncogenic pathways.
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