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Interactions between cancer-associated fibroblasts and tumor cells promote MCL-1 dependency in estrogen receptor-positive breast cancers

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Louault, Kevin | Bonneaud, Thomas, L | Séveno, Céline | Gomez-Bougie, Patricia | Nguyen, Frédérique | Gautier, Fabien | Bourgeois, Nathalie | Loussouarn, Delphine | Kerdraon, Olivier | Barillé-Nion, Sophie | Jézéquel, Pascal | Campone, Mario | Amiot, Martine | Juin, Philippe, P | Souazé, Frédérique

Edité par CCSD ; Nature Publishing Group [1987-....] -

International audience. 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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