The dual role of cyclin D1: Unraveling its tumor-promoting mechanisms and opportunities for therapeutics

Cyclin D1, a crucial cell cycle regulator, is well-known to be a strong oncogene that is often dysregulated or overexpressed in a variety of human malignancies. It is a key therapeutic target because of its typical role in promoting G1/S phase progression by phosphorylating the retinoblastoma protein (Rb) in a manner that is dependent on CDK4/6. Recent studies, however, reveal that cyclin D1 has a more complex and paradoxical in nature. In addition to its CDK-dependent oncogenic function, cyclin D1 participates in numerous CDK-independent carcinogenic associations. As a transcriptional modulator, it binds to and affects the activity of transcription factors and co-regulators. It also interacts with important elements of metabolic pathways and DNA damage repair to support tumor surviving, genome instability, and resistance to therapies. This duality offers an opportunity as well as a challenge. The challenge with cyclin D1-overexpressing tumors that either have Rb depletion or other bypass mechanisms is that CDK4/6 inhibitors are not very effective. However, the opportunity comes from the vulnerability that these partnerships cause. This review summarizes the dual role of cyclin D1 through exploring the oncogenic interactions and regulatory mechanisms underlying its dysregulation that drives cancer, as well as highlighting the possible therapeutic opportunities, revealing how targeting this pathway could improve precision oncology. This could help provide insight on how cancer precision therapy could be improved by targeting Cyclin D1 and the pathways that are associated to it.