Cancer-like Hallmarks of Endometriosis: The Role of Estrogen Signaling and Stem Cell Plasticity

Endometriosis is a chronic estrogen-dependent inflammatory disease affecting approximately 10% of women of reproductive age and characterized by ectopic endometrial-like tissue growth. Although traditionally considered a benign gynecological condition, increasing evidence indicates that endometriosis shares several molecular and cellular features with malignant processes, including enhanced proliferation, resistance to apoptosis, invasive behavior, and the ability to remodel the surrounding microenvironment. Recent studies suggest that dysregulated estrogen signaling, particularly the imbalance between estrogen receptor subtypes, plays a central role in driving these processes and may contribute to the persistence and progression of ectopic lesions. In parallel, also the involvement of stem or progenitor cells has been highly investigated because they may support lesion establishment, cellular plasticity, and long-term disease maintenance. These mechanisms overlap with pathways commonly involved in tumor initiation and progression. Recognizing endometriosis as a stem cell-driven and estrogen-dependent condition, the perspective, in both clinical management and therapeutic strategies fields, can change. Indeed, it is essential to emphasize that endometriosis is a benign condition and that the risk of developing an associated tumor is very low, approximately 1.5–2%. This review aims to discuss current evidence on the molecular aspects, focusing on estrogen signaling, stem cell-related mechanisms, and inflammatory and microenvironmental pathways that contribute to disease development. By highlighting these mechanisms, an integrated perspective on the pathophysiology of endometriosis is provided, also to outline potential implications for biomarker discovery and targeted therapeutic strategies.