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

These findings were validated in estrogen-deprived ER⁺ cell lines and patient-derived xenograft (PDX) models, where dormancy correlated with reduced CREB1 activity and tumor recurrence coincided with CREB1 reactivation. CREB1 inhibition—via small molecule or siRNA knockdown—effectively reversed CREB1, ER, and E2F1 transcriptional programs by downregulating the DDGs while upregulating the DUGs, and reduced cell proliferation and survival in endocrine- and CDK4/6 inhibitor-resistant ER⁺ breast cancer cells.

These findings establish CREB1 as a master regulator of transcriptional reprograming in relapsed ER⁺ breast cancers and highlight it as a promising therapeutic target for overcoming resistance to current endocrine and CDK4/6-based therapies.