2. Academic Validation
  3. Low BCL-xL expression in triple-negative breast cancer cells favors chemotherapy efficacy, and this effect is limited by cancer-associated fibroblasts

Low BCL-xL expression in triple-negative breast cancer cells favors chemotherapy efficacy, and this effect is limited by cancer-associated fibroblasts

  • Sci Rep. 2024 Jun 19;14(1):14177. doi: 10.1038/s41598-024-64696-z.
Lisa Nocquet 1 2 3,  Julie Roul 1 2 3 4,  Chloé C Lefebvre 1 2 3,  Laurine Duarte 1 2 3,  Mario Campone 1 3 4,  Philippe P Juin 5 6 7 8,  Frédérique Souazé 9 10 11
Affiliations

Affiliations

  • 1 INSERM, CNRS, CRCI2NA, Université de Nantes, 44000, Nantes, France.
  • 2 Equipe Labellisée LIGUE Contre le Cancer, Paris, France.
  • 3 SIRIC ILIAD, Nantes, Angers, France.
  • 4 ICO René Gauducheau, Saint Herblain, France.
  • 5 INSERM, CNRS, CRCI2NA, Université de Nantes, 44000, Nantes, France. philippe.juin@univ-nantes.fr.
  • 6 Equipe Labellisée LIGUE Contre le Cancer, Paris, France. philippe.juin@univ-nantes.fr.
  • 7 SIRIC ILIAD, Nantes, Angers, France. philippe.juin@univ-nantes.fr.
  • 8 ICO René Gauducheau, Saint Herblain, France. philippe.juin@univ-nantes.fr.
  • 9 INSERM, CNRS, CRCI2NA, Université de Nantes, 44000, Nantes, France. frederique.souaze@univ-nantes.fr.
  • 10 Equipe Labellisée LIGUE Contre le Cancer, Paris, France. frederique.souaze@univ-nantes.fr.
  • 11 SIRIC ILIAD, Nantes, Angers, France. frederique.souaze@univ-nantes.fr.
PMID: 38898061 DOI: 10.1038/s41598-024-64696-z
Abstract

Triple negative breast cancers (TNBC) present a poor prognosis primarily due to their resistance to chemotherapy. This resistance is known to be associated with elevated expression of certain anti-apoptotic members within the proteins of the Bcl-2 Family (namely Bcl-xL, Mcl-1 and Bcl-2). These regulate cell death by inhibiting pro-apoptotic protein activation through binding and sequestration and they can be selectively antagonized by BH3 mimetics. Yet the individual influences of Bcl-xL, Mcl-1, and Bcl-2 on the sensitivity of TNBC cells to chemotherapy, and their regulation by cancer-associated fibroblasts (CAFs), major components of the tumor stroma and key contributors to therapy resistance remain to be delineated. Using gene editing or BH3 mimetics to inhibit anti-apoptotic Bcl-2 Family proteins in TNBC line MDA-MB-231, we show that Bcl-xL and Mcl-1 promote Cancer cell survival through compensatory mechanisms. This cell line shows limited sensitivity to chemotherapy, in line with the clinical resistance observed in TNBC patients. We elucidate that Bcl-xL plays a pivotal role in therapy response, as its depletion or pharmacological inhibition heightened chemotherapy effectiveness. Moreover, Bcl-xL expression is associated with chemotherapy resistance in patient-derived tumoroids where its pharmacological inhibition enhances ex vivo response to chemotherapy. In a co-culture model of Cancer cells and CAFs, we observe that even in a context where Bcl-xL reduced expression renders Cancer cells more susceptible to chemotherapy, those in contact with CAFs display reduced sensitivity to chemotherapy. Thus CAFs exert a profound pro-survival effect in breast Cancer cells, even in a setting highly favoring cell death through combined chemotherapy and absence of the main actor of chemoresistance, Bcl-xL.

Keywords

Apoptosis; BCL-2 family; Breast cancer; Cancer-associated fibroblasts; Chemotherapy.

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