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.

Hearing loss-associated protein gasdermin E (GSDME), an effector of secondary necrosis, has been identified in a new pathway of programmed cell death (PCD). GSDME epigenetic silencing and mutations resulting in loss-of-function have been reported in cancer tissues. Additionally, GSDME upregulation inhibits tumor proliferation as well as colony forming ability, and reduces the incidence of lymphatic metastasis, demonstrating that GSDME may act as a tumor suppressor. Here, we have focused on the molecular mechanisms of GSDME-mediated PCD, and tried to reveal the crosstalk between this cell death pathway and apoptosis, autophagy, GSDMD-mediated pyroptosis. Moreover, we concluded the anti-cancer activity of GSDME include forming permeable membranes, and triggering anti-cancer immunity. Thus, GSDME was potential to be a novel target for cancer prevention and treatment.

MicroRNAs (miRNAs) are a class of non-coding RNA sequences that regulate gene expression post-transcriptionally. The miR-99 family, which is highly evolutionarily conserved, comprises three homologs: miR-99a, miR-99b, and miR-100. Its members are under-expressed in most cancerous tissues, suggesting their cancer-repressing properties in multiple cancers; however, in some contexts, they also promote malignant lesion progression. MiR-99 family members target numerous genes involved in various tumor-related processes such as tumorigenesis, proliferation, cell-cycle regulation, apoptosis, invasion, and metastasis. We review the recent research on this family, summarize its implications in cancer, and explore its potential as a biomarker and cancer therapeutic target. This review contributes to the clinical translation of the miR-99 family members.

Higher cyclin-dependent kinase (CDK7) expression is a character of breast cancer and indicates poor prognosis. Inhibiting CDK7 exhibited effective cancer cell suppression which implies the potential of CDK7 inhibition to be a method for anti-cancer treatment. Our study aimed to explore a novel mechanism of CDK7 inhibition for suppressing breast cancer cell survival. Here, we proved inhibiting CDK7 repressed breast cancer cell proliferation and colony formation and increased the apoptotic cell rate, with p53 and GSDME protein level elevation. When p53 was suppressed in MCF-7 cells, the decline of GSDME expression and associated stronger proliferation and colony formation could be observed. Since downregulation of GSDME was of benefit to breast cancer cells, p53 inhibition blocked the elevation of GSDME induced by CDK7 inhibition and retrieved cells from the tumor suppressive effect of CDK7 inhibition. Therefore, CDK7 inhibition exerted a negative effect on breast cancer cell proliferation and colony formation in a p53–GSDME dependent manner. These results revealed the CDK7–p53–GSDME axis could be a pathway affecting breast cancer cell survival.