Why (multi)targeting of cyclin-dependent kinases is a promising therapeutic option for hormone-positive breast cancer and beyond

Estrogens, via induction of their specific receptors (e.g., ER-alpha), regulate cell proliferation, differentiation and morphogenesis in mammary epithelium. Cell-cycle progression is driven by activation of complexes consisting of cyclin-dependent kinases (CDKs) and cyclins, which also modulate the activity of ER-alpha. Loss of control over the cell-cycle results in accelerated cell division and malignant transformation. Thus, a reciprocal relation exists between estrogen signaling and cell proliferation. Based on these findings, a new concept was developed to reduce ER-alpha activity and bring the cell-cycle in transformed cells to heel. Prevention of ER-alpha activation and control over the deregulated cell cycle was achieved by supplementation with pharmacological CDK inhibitors alone or in combination with selective antiestrogens.