Adiponectin Influences the Behavior of Stem Cells in Hormone-Resistant Breast Cancer

In the breast tumor microenvironment (TME), adipocytes exert a selective pressure on the behavior of breast cancer stem cells (BCSCs), which are involved in endocrine therapy resistance. In obesity, adipocytes secrete reduced levels of adiponectin, which promotes the growth and progression of ERα-positive breast cancer (BC). Here, we examined how low adiponectin levels affect the enrichment of the BCSC subpopulation and the mechanisms contributing to the maintenance of endocrine therapy resistance in BC. Flow cytometry, qRT-PCR, and Western blotting analysis were performed to assess stemness, the cell cycle, and apoptosis markers in MCF-7 wild-type (WT) and tamoxifen-resistant (TR) mammospheres. nLC-MS/MS was employed to profile and compare the proteome of BCSCs. Differentially expressed proteins were intersected with data from the Metacore^TM dataset. Our study demonstrated that adiponectin increased the percentage of CD44⁺/CD24^-/ALDH1⁺ stem-like cells in TR MCF-7 mammospheres. Specifically, adiponectin contributed to the maintenance of BCSC bulk in TR MCF-7 cells through a slow cycling rate, supported by decreased levels of Cyclin D1 and Ki67 and increased p21 and p27 expression, and through escape from apoptosis, sustained by reduced ROS production and preserved maintenance of mitochondrial membrane potential. Our results provide new insights into the contribution of adiponectin to poor ERα-positive BC outcomes. Deeply understanding adiponectin's role in stemness may disclose novel therapeutic approaches to treat hormone-resistant obese BC patients.