1. Academic Validation
  2. Targeting Mutated p53 Dependency in Triple-Negative Breast Cancer Cells Through CDK7 Inhibition

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

  • Front Oncol. 2021 May 24;11:664848. doi: 10.3389/fonc.2021.664848.
Jingyu Peng 1 2 Ming Yang 1 Ran Bi 2 3 Yueyuan Wang 1 2 Chunxi Wang 3 Xue Wei 1 Zhihao Zhang 1 Xiao Xie 1 Wei Wei 2
Affiliations

Affiliations

  • 1 Department of Breast Surgery, The First Hospital of Jilin University, Changchun, China.
  • 2 Key Laboratory of Organ Regeneration & Transplantation of the Ministry of Education, Institute of Translational Medicine, The First Hospital of Jilin University, Changchun, China.
  • 3 Department of Urology, The First Hospital of Jilin University, Changchun, China.
Abstract

Background: Cyclin-dependent kinase 7 (CDK7) is crucial for cell cycle progression and gene expression transcriptional regulation, which are often not assessed in Cancer developing process. CDK7 inhibitors have emerged as promising drugs for treating diverse cancers, including breast Cancer. However, the mechanism behind its Anticancer effect has not been well investigated. Here, the possible mechanism of CDK7 inhibitors for treating human triple-negative breast Cancer (TNBC) has been studied.

Methods: The effects of CDK7 inhibitors on breast Cancer cells have been identified by measuring cell viability (Cell Counting Kit-8) and cell proliferation and calculating colony formation. The short hairpin RNA and short interfering RNA were used for the construction of knockdown cells. To assess the expression of associated proteins, western blot was used.

Results: This study confirmed that, compared to hormone receptor-positive breast Cancer cells, TNBC cells were more sensitive to THZ1, a novel CDK7 Inhibitor. THZ1 treatment specifically downregulated mutated p53 in a dose- and time-dependent manner in TNBC cells with p53 mutation. Another CDK7 Inhibitor, LDC4297, also potently interfered with the expression of mutated p53. Furthermore, endogenous CDK7 expression was positively correlated with the levels of mutated p53 in TNBC cells with p53 mutation. Downregulating mutated p53 expression significantly suppressed the proliferation of TNBC cells with p53 mutation.

Conclusion: Our findings demonstrated that targeting CDK7 was an effective approach for the treatment of TNBC with p53 mutation.

Keywords

CDK7 inhibition; THZ1; cancer treatment; mutated p53; targeted therapy; triple-negative breast cancer.

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