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

• Published in: Scientific reports 2024-06, Vol.14 (1), p.14177-10, Article 14177
• Main Authors: Nocquet, Lisa, Roul, Julie, Lefebvre, Chloé C., Duarte, Laurine, Campone, Mario, Juin, Philippe P., Souazé, Frédérique
• Format: Article
• Language: English
• Subjects: 631/67; 631/80; Antineoplastic Agents - pharmacology; Apoptosis; Apoptosis - drug effects; BCL-2 family; Bcl-2 protein; Bcl-x protein; bcl-X Protein - genetics; bcl-X Protein - metabolism; Biochemistry, Molecular Biology; Breast cancer; Cancer; Cancer-associated fibroblasts; Cancer-Associated Fibroblasts - drug effects; Cancer-Associated Fibroblasts - metabolism; Cell culture; Cell death; Cell Line, Tumor; Cell survival; Cell Survival - drug effects; Chemoresistance; Chemotherapy; Drug Resistance, Neoplasm - genetics; Female; Fibroblasts; Gene Expression Regulation, Neoplastic - drug effects; Genome editing; Genomics; Humanities and Social Sciences; Humans; Life Sciences; Mcl-1 protein; Medical prognosis; multidisciplinary; Myeloid Cell Leukemia Sequence 1 Protein - genetics; Myeloid Cell Leukemia Sequence 1 Protein - metabolism; Pharmaceutical sciences; Pharmacology; Proto-Oncogene Proteins c-bcl-2 - antagonists & inhibitors; Proto-Oncogene Proteins c-bcl-2 - genetics; Proto-Oncogene Proteins c-bcl-2 - metabolism; Science; Science (multidisciplinary); Stroma; Triple Negative Breast Neoplasms - drug therapy; Triple Negative Breast Neoplasms - genetics; Triple Negative Breast Neoplasms - metabolism; Triple Negative Breast Neoplasms - pathology
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-024-64696-z

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.