Dormancy exit correlates with CREB1 reactivation that is a potential target to overcome endocrine therapy resistance in ER⁺ breast cancer cells

Estrogen receptor-positive (ER⁺) breast cancers often recur years after endocrine therapy, due to tumor cells escaping a dormant state. Mechanisms underlying dormancy and recurrence are poorly understood. We identify CREB1 as a key regulator of ER⁺ tumor dormancy and recurrence. Analysis of dormant tumor samples from aromatase inhibitor-treated patients revealed 1,057 dormancy-downregulated genes (DDGs) and 1,142 dormancy-upregulated genes (DUGs). Pathway analyses implicated CREB1, together with ER and E2F1, as central regulators of these gene programs. Similar gene changes were confirmed in ER⁺ cell and patient-derived xenograft (PDX) tumor models of estrogen deprivation-induced dormancy and reversed upon acquired estrogen independence and tumor recurrence. CREB1 inhibition suppressed DDG expression, induced DUGs, and reduced survival of endocrine- and CDK4/6 inhibitor-resistant ER⁺ breast cancer cells. Together, the findings establish CREB1 as a key regulator of transcriptional reprogramming during relapse and a promising therapeutic target to overcome endocrine resistance.