Fig. 2

Resistance of CDK4/6 inhibitors induced by gBRCA2 mutation in BC: In gBRCA2 wild type BC cells, E2 binding to ERα promotes CDK4/6 to form a complex with Cyclin D, which is followed by phosphorylation of Rb1 and release of the transcription factor E2F. Then E2F promotes the cell cycle from G1 mitosis into S phase, leading to DNA replication [80]. In gBRCA2 mutation BC cells, this is often accompanied by loss of Rb1, and reduced inhibition of E2F by Rb1, which promotes cell cycle progression. Rb1 deletion leads to the loss of downstream targets of CDK4/6, resulting in resistance to CDK4/6 inhibitors in gBRCA2-mutated BC [81, 82].