Overcoming endocrine-resistance is the major challenge in treating Estrogen receptor (ER)-positive breast cancer. Breast Cancer Stem Cells (BCSCs) are blamed to be the driving force behind poor clinical outcomes and therapeutic resistance. Tumor microenvironment (TME) exerts a selective pressure on the tumor, supporting BCSCs behavior. The most prevalent cellular component of breast TME is represented by adipocytes, which secrete reduced levels of adiponectin in obesity, promoting ERα-positive breast cancer growth and progression. We examined the impact of low adiponectin levels on the enrichment of BCSC subpopulations and the molecular mechanisms by which this may contribute to hormone-resistance in breast cancer.