Adipocyte–Tumor Crosstalk and CSC-Associated Doxorubicin Response in Breast Cancer Mammospheres: Role of Licorice Root Extract

The response of breast cancer to chemotherapy is strongly influenced by tumor–microenvironment interactions and the presence of cancer stem-like cells (CSCs), which are associated with therapy resistance. The aim of this study was to investigate whether modulation of adipocyte–tumor crosstalk by licorice root extract (LRE) could influence doxorubicin response in CSC-enriched MCF-7 mammospheres. MCF-7 cells were pretreated with conditioned media derived from preadipocytes, mature adipocytes, or LRE-treated mature adipocytes, or were directly exposed to LRE, and subsequently cultured as mammospheres. CSC enrichment was supported by increased expression of CD44 and CD133. Mature adipocyte-conditioned medium promoted the formation of larger and more compact spheroids, reduced intracellular reactive oxygen species (ROS) and apoptosis, and decreased doxorubicin uptake. In contrast, conditioned medium from LRE-treated adipocytes partially counteracted these effects by increasing oxidative stress, apoptotic response, and intracellular doxorubicin accumulation. Collectively, these findings support the involvement of adipocyte–tumor crosstalk in modulating functional parameters associated with doxorubicin responsiveness and suggest that modulation of the adipose microenvironment by LRE may represent a promising area for further investigation in the context of microenvironment-driven chemoresistance.