Figure 5. Summary for the role of proteolytic regulation of KLF4 in breast carcinogenesis via regulating TGF-β and estrogen signaling.
Defective regulation of estrogen receptor (ER) and transforming growth factor beta (TGF-β) signaling pathways can predispose breast cells towards carcinogenesis. Our recent findings have revealed a previously unknown mechanism that centers on the interplay between KLF4, an oncogenic transcriptional factor, and VHL/VBC (E3 ligase) as well as between VHL and β-TRCP/SCF (E3 ligase) in cell cycle control and proliferation. Their functional interaction is critical in orchestrating the crosstalk between ER and TGF-β signaling pathways, which in turn determines whether breast cells retain their homeostasis or are transformed to initiate oncogenic growth. Our observations have provided insight into the pathological mystery previously observed by us and others that over 70% of human mammary cancers exhibited cellular accumulation of KLF4 and decreased levels of VHL protein and that disruption in β-TRCP function in mice could results in tumor initiation and progression. We are currently studying the molecular basis of the interplay between KLF4 and VHL/VBC as well as VHL and β-TRCP/SCF in their regulation of ER and TGF-β signal transduction and determining how impaired KLF4 proteolytic regulation due to dysregulated VHL/VBC Or β-TRCP/SCF would impact breast tumorigenesis using a breast cancer animal model (Fig. 5). Outcomes from this project could provide a more effective strategy to modulate the ER signaling pathway by exploiting components of the β-TRCP/SCF - VHL/VBC - KLF4 cascade. Controlling the ER signaling pathway has long been a key focus in the field to develop new methods for chemoprevention and endocrine therapy for breast cancer treatment. This project is recently funded by NIH/NCI R01 grant (CA202948).