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. 2023 Mar 14;15(6):1763. doi: 10.3390/cancers15061763

Figure 1.

Figure 1

Pathways potentially contributing to endocrine treatment resistance (simplified representation) [14,15]. AKT: AKT murine thymoma viral oncogene; CDK4/6: cyclin-dependent kinase 4/6; E2: estradiol; E2F: transcription factor; ERalpha: estrogen receptor alpha; ESR1: estrogen receptor 1 gene; mTOR: mammalian target of rapamycin; PI3K: phosphatidylinositol 3-kinase; Rb: retinoblastoma protein; SERD: selective estrogen receptor degrader; SERM: selective estrogen receptor modulator. In HR-positive BC cells, different mechanisms may lead to hyperactivation of the cyclin D-CDK4/6-retinoblastoma pathway. The activation of the PI3K-AKT-mTOR pathway can increase cyclin D levels or enhance its activity through post-translational mechanisms. Moreover, in contrast to triple-negative BC cells, where Rb is mostly absent or dysfunctional, in HR-positive BC cells, it is usually retained. Genomic factors, which encode for the endogenous inhibition of the CDK4/6 or are involved in the transcription of the estrogen receptor, explain why CDK4/6 plays a significant role in HR-positive BC in special. Regarding resistance mechanisms, mutations (e.g., FAT1) and a loss of functional Rb in particular are discussed to be associated with de novo and acquired CDK4/6i resistance [16].