Targeting Mutated p53 Dependency in Triple-Negative Breast Cancer Cells Through CDK7 Inhibition

Area of Science:

• Oncology
• Molecular Biology
• Cancer Research

Background:

• Cyclin-dependent kinase 7 (CDK7) plays a vital role in cell cycle progression and gene transcription.
• CDK7 inhibitors are emerging as potential therapeutics for various cancers, including breast cancer.
• The precise anticancer mechanisms of CDK7 inhibitors, particularly in triple-negative breast cancer (TNBC), require further investigation.

Purpose of the Study:

• To investigate the mechanism of CDK7 inhibitors in treating human triple-negative breast cancer (TNBC).
• To evaluate the efficacy of CDK7 inhibition in TNBC cells, especially those with p53 mutations.

Main Methods:

• Cell viability, proliferation, and colony formation assays were used to assess the effects of CDK7 inhibitors.
• Short hairpin RNA (shRNA) and short interfering RNA (siRNA) were employed for gene knockdown.
• Western blotting was utilized to analyze the expression of relevant proteins.

Main Results:

• TNBC cells exhibited greater sensitivity to the CDK7 inhibitor THZ1 compared to hormone receptor-positive cells.
• THZ1 treatment led to a dose- and time-dependent downregulation of mutated p53 in TNBC cells harboring p53 mutations.
• The CDK7 inhibitor LDC4297 also effectively reduced mutated p53 expression.
• Endogenous CDK7 levels positively correlated with mutated p53 levels in p53-mutated TNBC cells.
• Suppression of mutated p53 expression significantly inhibited TNBC cell proliferation.

Conclusions:

• Targeting CDK7 presents a viable therapeutic strategy for TNBC with p53 mutations.
• CDK7 inhibition, particularly through downregulation of mutated p53, offers a promising approach for TNBC treatment.