cAMP response element-binding protein: A credible cancer drug target

Despite advancements in radiotherapy, chemotherapy, endocrine therapy, targeted therapy, and immunotherapy, resistance to therapy remains a pervasive challenge in oncology, in part owing to tumor heterogeneity. Identifying new therapeutic targets is key to addressing this challenge because it can both diversify and enhance existing treatment options, particularly through combination regimens. The cAMP response element-binding protein (CREB) is a transcription factor involved in various biological processes. It is aberrantly activated in several aggressive cancer types, including breast cancer. Clinically, high CREB expression is associated with increased breast tumor aggressiveness and poor prognosis. Functionally, CREB promotes breast cancer cell proliferation, survival, invasion, metastasis, as well as therapy resistance by deregulating genes related to apoptosis, cell cycle, and metabolism. Targeting CREB with small molecule inhibitors has demonstrated promise in preclinical studies. This review summarizes the current understanding of CREB mechanisms and their potential as a therapeutic target. SIGNIFICANCE STATEMENT: cAMP response element-binding protein (CREB) is a master regulator of multiple biological processes, including neurodevelopment, metabolic regulation, and immune response. CREB is a putative proto-oncogene in breast cancer that regulates the cell cycle, apoptosis, and cellular migration. Preclinical development of CREB-targeting small molecules is underway.