Expression of Phosphorylated BRD4 Is Markedly Associated with the Activation Status of the PP2A Pathway and Shows a Strong Prognostic Value in Triple Negative Breast Cancer Patients

Simple Summary The use of BRD4 inhibitors has emerged as a novel therapeutic approach in a wide variety of tumors including the triple negative breast cancer. Moreover, PP2A has been proposed as the phosphatase involved in regulating BRD4 phosphorylation and stabilization. Our aim was to evaluate for the first time the clinical impact of BRD4 phosphorylation in triple negative breast cancer patients and as well as its potential linking with the PP2A activation status in this disease. Our findings are special relevant since they suggest the prognostic value of BRD4 phosphorylation levels, and the potential clinical usefulness of PP2A inhibition markers to anticipate response to BRD4 inhibitors. The bromodomain-containing protein 4 (BRD4), a member of the bromodomain and extra-terminal domain (BET) protein family, has emerged in the last years as a promising molecular target in many tumors including breast cancer. The triple negative breast cancer (TNBC) represents the molecular subtype with the worst prognosis and a current therapeutic challenge, and TNBC cells have been reported to show a preferential sensitivity to BET inhibitors. Interestingly, BRD4 phosphorylation (pBRD4) was found as an alteration that confers resistance to BET inhibition and PP2A proposed as the phosphatase responsible to regulate pBRD4 levels. However, the potential clinical significance of pBRD4, as well as its potential correlation with the PP2A pathway in TNBC, remains to be investigated. Here, we evaluated the expression levels of pBRD4 in a series of 132 TNBC patients. We found high pBRD4 levels in 34.1% of cases (45/132), and this alteration was found to be associated with the development of patient recurrences (p = 0.007). Interestingly, BRD4 hyperphosphorylation predicted significantly shorter overall (p < 0.001) and event-free survival (p < 0.001). Moreover, multivariate analyses were performed to confirm its independent prognostic impact in our cohort. In conclusion, our findings show that BRD4 hyperphosphorylation is an alteration associated with PP2A inhibition that defines a subgroup of TNBC patients with unfavorable prognosis, suggesting the potential clinical and therapeutic usefulness of the PP2A/BRD4 axis as a novel molecular target to overcome resistance to treatments based on BRD4 inhibition.

Automated summary

BRD4 phosphorylation plays a crucial role in triple negative breast cancer, with high levels associated with patient recurrence. This phosphorylation predicts shorter overall and event-free survival, making it an independent prognostic factor in this disease. These findings highlight the potential clinical and therapeutic usefulness of the PP2A/BRD4 axis as a novel molecular target to overcome resistance to BRD4 inhibitors.