Endocrine–Immune Conditioning and NET-Mediated Dormancy Awakening in ER+ Breast Cancer

Late distant recurrence in estrogen receptor-positive (ER+) breast cancer raises the question of how disseminated tumor cells resume proliferation years after primary tumor resection. We propose two coupled processes: endocrine–immune conditioning of the local niche and neutrophil extracellular trap (NET)-mediated dormancy awakening. In the first, ERα-associated signaling is proposed to alter neutrophil recruitment and activation, favoring NET formation and local persistence near dormant cells. In the second, NET-associated proteases remodel basement-membrane laminin, generating matrix signals that activate integrin α3β1-dependent signaling and intracellular YAP in adjacent tumor cells, promoting cell-cycle reentry. Estrogen-dependent neutrophil reprogramming and NET-mediated awakening have experimental support in separate systems, including mammary involution and a postresection breast cancer dormancy model in the lung. Distant perivascular niches support dormancy. We propose that endocrine–immune conditioning engages NET-mediated awakening of dormant ER+ cells within these niches. PER2 loss is proposed to reinforce endocrine–immune conditioning through ERα stabilization, while local estrogen production, complement and coagulation shape niche permissiveness. Spatial analysis of primary tumors can test spatial organization and its association with subsequent recurrence. Distant-site studies and functional dormancy models are needed to test local endocrine–immune conditioning and NET-dependent reactivation after resection. This model links host endocrine–immune conditions to dormant tumor-cell awakening.