Figure 1.

The role of the cyclin D1–CDK4/6–RB pathway in breast cancer.

The role of the cyclin D1–CDK4/6-RB pathway in breast cancer cells, including cross talk with other oncogenic signaling pathways. Mitogenic forces including ER transcriptional activity and signaling through ERBB2/PI3K/AKT/mTOR increase cyclin D1 levels, activating CDK4/6 and promoting cellular progression to the S phase. There is extensive crosstalk between the PI3K and CDK4/6 pathways: not only does PI3K pathway activity increase cyclin D1 levels, but the cyclin D–CDK4/6 complex can modulate TSC2 phosphorylation and hence mTORC1 activity. Combined inhibition of CDK4/6 and nodes in the PI3K pathway can thus maximally suppress mTORC1 activity as well as RB phosphorylation, inhibiting two promoters of S phase progression. Furthermore, suppression of E2F activity can modulate the tumor cell epigenome, rendering tumor cells more immunogenic and providing a rationale for CDK4/6-immunotherapy combinations.

AR, androgen receptor; EGFR, epidermal growth factor receptor; ER, estrogen receptor; HER, human epidermal growth factor receptor; mTOR, mammalian target of rapamycin; PI3K, phosphoinositide-3-kinase; RB, retinoblastoma protein, TSC2, tuberous sclerosis complex 2 (tuberin).