Hsp27 downregulation decreases β-catenin expression and sensitizes triple-negative breast cancer cells to doxorubicin

Triple-negative breast cancer (TNBC) is a highly complex disease with limited treatment options available. More resources are needed to develop effective therapies. In breast cancer, the involvement of both the β-catenin and Hsp27 pathways is a well-established fact. Although beta-catenin and Hsp27 signaling pathways are known to play crucial roles in the progression of TNBC, their particular contributions towards the response of TNBC patients to treatment still remain unclear. The aim of this study was to determine the relationship between β-catenin and Hsp27 signaling pathways and the response of human TNBC cell lines to two specific drugs, CisPt and DOXO. The DOXO and CisPt effects on MDA-MB-231 and MCF-10A cell lines viability were evaluated by MTT assay. Additionally, apoptosis and senescence were evaluated. Changes in mRNA, protein levels, and subcellular protein localizations were analyzed using RT-PCR, Western blot and immunofluorescence, respectively. Hsp27 downregulation and β-catenin inhibition were studied to investigate their effects on breast cancer cells responses. MDA-MB-231 cells exhibited less sensitivity to DOXO and CisPt compared to MCF-10A cells. In CisPt-treated MDA-MB-231 cells, there was a significant decrease in total and active β-catenin levels, as well as Hsp27. The decrease in protein expression was linked with an increased apoptosis and the absence of senescence. Upon treatment with DOXO, both total β-catenin and Hsp27 in MDA-MB-231 cells increased. However, the increase in β-catenin and Hsp27 levels after DOXO treatment was found to be mainly associated with senescence instead of apoptosis. Moreover, the exposure to DOXO and CisPt increased the subcellular localization of active β-catenin in the nucleolus, particularly in MDA-MB-231. Inhibiting Hsp27 expression sensitized TNBC cells to DOXO therapy by increasing apoptosis and decreasing senescence. These findings indicate that these drugs induce modifications in the β-catenin pathway, alter Hsp27 levels, and cause variations in cellular localization. The effect on cell fate, whether apoptosis or senescence, appears to be specific to each drug. Targeting Hsp27 downregulation and β-catenin inhibition could enhance the chemosensitivity of cancer cells, potentially increasing the efficacy of DOXO in TNBC treatment.