HAL Id: inserm-01991165
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Submitted on 23 Jan 2019
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Interactions between cancer-associated fibroblasts and tumor cells promote MCL-1 dependency in estrogen
receptor-positive breast cancers
Kevin Louault, Thomas Bonneaud, Céline Séveno, Patricia Gomez-Bougie, Frédérique Nguyen, Fabien Gautier, Nathalie Bourgeois, Delphine Loussouarn,
Olivier Kerdraon, Sophie Barillé-Nion, et al.
To cite this version:
Kevin Louault, Thomas Bonneaud, Céline Séveno, Patricia Gomez-Bougie, Frédérique Nguyen, et
al.. Interactions between cancer-associated fibroblasts and tumor cells promote MCL-1 dependency
in estrogen receptor-positive breast cancers. Oncogene, Nature Publishing Group, 2019, Epub ahead
of print. �10.1038/s41388-018-0635-z�. �inserm-01991165�
Oncogene
https://doi.org/10.1038/s41388-018-0635-z A R T I C L E
Interactions between cancer-associated fi broblasts and tumor cells promote MCL-1 dependency in estrogen receptor-positive breast cancers
K. Louault
1,2●T. L Bonneaud
1,2●C. Séveno
1,2●P. Gomez-Bougie
2,3●F. Nguyen
1,4●F. Gautier
1,2,5●N. Bourgeois
1,2●D. Loussouarn
6●O. Kerdraon
2,5●S. Barillé-Nion
1,2●P. Jézéquel
1,2,5●M. Campone
1,2,5 ●M. Amiot
2,3●P. P. Juin
1,2,5,7●F. Souazé
1,2,7Received: 20 June 2018 / Revised: 22 November 2018 / Accepted: 23 November 2018
© The Author(s) 2019. This article is published with open access
Abstract
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 fi broblasts (bCAFs) in a manner that de fi nes 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 bene fi cial for targeted apoptosis of breast tumor ecosystems, even in a subtype where MCL-1 dependency is not intrinsically driven by oncogenic pathways.
Introduction
Breast cancer is a heterogeneous disease that encompasses distinct molecular subtypes. The majority of mammary
carcinomas express, in a signi fi cant portion of malignant cells, hormone receptors for estrogen (ER) and/or proges- terone (PgR). These breast cancers include luminal A ones (LUM A), and luminal B ones (LUM B), less prevalent but signi fi cantly more aggressive and of poor prognosis.
Patients are treated by endocrine therapy, with, in general, additional chemotherapy for LUM B. As therapy resistance remains a major obstacle to the successful treatment of these cancers new more ef fi ciently cytotoxic approaches need to be identi fi ed.
Proteins of the BCL-2 family critically regulate the mitochondrial apoptotic pathway by engaging a network of intracellular interactions through which BCL-2 homologues (BCL-2, BCL-xL, and MCL-1) exert distinct, com- plementary anti-apoptotic activities [1]. These activities need to be overcome for therapy to be ef fi cient. Recipro- cally, direct inhibition of anti-apoptotic proteins may suf fi ce to enhance cancer cell vulnerability and promote apoptosis [2]. Targeted mitochondrial apoptosis is now achievable by selective BH3 mimetic inhibitors. ABT-737 (a preclinical lead compound) and its orally available equivalent ABT- 263 (Navitoclax) bind to and inhibit BCL-2 and BCL-xL but not MCL-1, while ABT-199 (Venetoclax) preferentially targets BCL-2. The latter compound presents the clinical advantage to avoid dose-dependent thrombocytopenia, a
* P. P. Juin
philippe.juin@univ-nantes.fr
* F. Souazé
frederique.souaze@univ-nantes.fr
1
CRCINA, Team 8, INSERM, Université d ’ Angers, Université de Nantes, Nantes, France
2
SIRIC ILIAD, Angers, Nantes, France
3
CRCINA, Team 10, INSERM, Université d ’ Angers, Université de Nantes, Nantes, France
4
ONIRIS, Nantes Atlantic College of Veterinary Medicine Food Science and Engineering, Animal Cancers, Nantes, France
5
ICO René Gauducheau, Saint Herblain, France
6
Service d ’ Anatomie Pathologique, CHU Nantes, Nantes, France
7
CNRS GDR3697 Micronit, Tours, France
Supplementary information The online version of this article (https://
doi.org/10.1038/s41388-018-0635-z) contains supplementary material, which is available to authorized users.
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