Mutant p53 Regulates Pyruvate Dehydrogenase Kinase 1 (PDK1) to Promote Proliferation and Migration in Breast Cancer

Area of Science:

• Oncology
• Molecular Biology
• Biochemistry

Background:

• The tumor suppressor p53 is frequently mutated in cancers, leading to loss of function and acquisition of oncogenic properties.
• Stabilization of mutant p53 (mutp53) is crucial for its gain-of-function activities.
• TP53 mutations are common in breast cancer, contributing to tumor progression.

Purpose of the Study:

• To elucidate the novel mechanism by which pyruvate dehydrogenase kinase 1 (PDK1) influences wild-type and mutant p53.
• To investigate PDK1's role in facilitating proliferation and migration in TP53 mutant breast cancer.
• To explore PDK1 as a potential therapeutic target in TP53 mutant breast cancer.

Main Methods:

• Identified PDK1 as a transcriptional target of wild-type p53 and investigated its activation by the EGR1 axis in mutp53 cells.
• Examined PDK1's interaction with mutp53 and its effect on mutp53 protein degradation.
• Assessed the therapeutic efficacy of combining PDK1 inhibition with APR-246 in xenograft models of TP53 mutant breast cancer.

Main Results:

• PDK1 is a direct transcriptional repression target of wild-type p53 and is transcriptionally activated by EGR1 in mutp53 cells.
• PDK1 binds to mutp53, inhibiting its degradation and promoting its accumulation, thus enhancing breast cancer malignancy.
• Combined inhibition of PDK1 and APR-246 demonstrated increased therapeutic effects in xenograft tumors.

Conclusions:

• Mutant p53 upregulates PDK1, creating a positive feedback loop that enhances p53 protein stability and promotes breast cancer malignancy.
• PDK1 plays a critical role in the oncogenic functions of mutant p53 in breast cancer.
• Targeting PDK1 presents a promising therapeutic strategy for treating TP53 mutant breast cancer, potentially in combination with existing therapies like APR-246.