Abstract
ABSTRACTTriple negative breast cancers (TNBC) present a poor prognosis primarily due to their resistance to chemotherapy. This resistance is 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), which regulate cell apoptosis by inhibiting the activation of pro-apoptotic proteins through binding and sequestration. BH3 mimetics, inhibitors of these anti-apoptotic proteins, have been developed to disrupt this interaction and induce apoptosis. Furthermore, within the tumor microenvironment, cancer-associated fibroblasts (CAFs) have been identified as key contributors to therapy resistance. In this work, we aim to delineate the influence of BCL-xL, MCL-1, and BCL-2 on the sensitivity of TNBC cells to chemotherapy, while also considering the stromal microenvironment. By utilizing engineered cell lines deficient in BCL-2 family proteins and BH3 mimetics, we show that BCL-xL and MCL-1 promote the survival of two TNBC cell lines by compensatory mechanisms. Moreover, we observe limited chemotherapy effectiveness in both cell lines, confirming 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. Our findings strongly suggest that BCL-xL contribute to chemotherapy resistance in patient-derived tumoroids as well. In a co-culture model of MDA-MB-468 cells and CAFs, we observe that even in a context where BCL-xL inhibition renders cancer cells more susceptible to chemotherapy, those in contact with CAFs display reduced sensitivity to chemotherapy. This underscores the protective influence of CAFs on tumor cells, emphasizing their profoundly pro-survival effect in breast cancer cells, even in a setting highly conducive to apoptosis through combined chemotherapy and BCL-xL inhibition.
Publisher
Cold Spring Harbor Laboratory