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

Abstract

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.

Kinome-Wide siRNA Screening Identifies DYRK1B as a Potential Therapeutic Target for Triple-Negative Breast Cancer Cells

“…TNBC patients currently treated with conventional chemotherapy, including anthracycline and taxane, do not exhibit a striking increase in pathological complete response (pCR), ranging 30–40% for early stage TNBC patients [ 1 ]. Though several biomarkers have been reported as diagnostic and prognostic candidates [ 3 , 4 ], a therapeutic target is still an urgent need for TNBC patients.…”

PP2A and cancer epigenetics: a therapeutic opportunity waiting to happen

“…Therefore, restoring PP2A activity may be important for maximizing the therapeutic efficacy of BET inhibitors. For example, the combination of the PP2A-activating compound, perphenazine and JQ1 resulted in a synergistic loss of triple negative breast cancer cell viability ( 69 , 73 ). In addition to the transcriptional control of MYC, PP2A also directly post-translationally regulates MYC protein stability ( 20 ).…”

Research progress on the relationship between the TOR signaling pathway regulator, epigenetics, and tumor development

“…As a transcriptional and epigenetic regulator that plays an important role in cancer development, BRD4 accumulates at euchromatic sites to stimulate gene expression (Donati et al, 2018). BRD4 is shown to be more likely to be associated with activating acetylation marks after being phosphorylated by casein kinase II (CK2), making BRD4 hyperphosphorylation a predictor of poor prognosis in several malignancies (Wu et al, 2013;Sanz-Álvarez et al, 2021). Additionally, as shown by ERK phosphorylation and increased kinase activity, downregulation of CK2 can result in suppression of the mammalian target of rapamycin (mTOR) cascade, downregulation of Raptor expression levels, and stimulation of the extracellular signaling-regulated protein kinase 1/2 (ERK1/2) signaling mechanism (Olsen et al, 2012).…”