PP2A inhibition determines poor outcome and doxorubicin resistance in early breast cancer and its activation shows promising therapeutic effects

Abstract

The protein phosphatase 2A (PP2A) is a key tumor suppressor which has emerged as a novel molecular target in some human cancers. Here, we show that PP2A inhibition is a common event in breast cancer and identified PP2A phosphorylation and deregulation SET and CIP2A as molecular contributing mechanisms to inactivate PP2A. Interestingly, restoration of PP2A activity after FTY720 treatment reduced cell growth, induced apoptosis and decreased AKT and ERK activation. Moreover, FTY720 led to PP2A activation then enhancing doxorubicin-induced antitumor effects both in vitro and in vivo. PP2A inhibition (CPscore: PP2A phosphorylation and/or CIP2A overexpression) was detected in 27% of cases (62/230), and associated with grade (p = 0.017), relapse (p < 0.001), negative estrogen (p < 0.001) and progesterone receptor expression (p < 0.001), HER2-positive tumors (p = 0.049), Ki-67 expression (p < 0.001), and higher AKT (p < 0.001) and ERK (p < 0.001) phosphorylation. Moreover, PP2A inhibition determined shorter overall (p = 0.006) and event-free survival (p = 0.003), and multivariate analysis confirmed its independent prognostic impact. Altogether, our results indicate that PP2A is frequently inactivated in breast cancer and determines worse outcome, and its restoration using PP2A activators represents an alternative therapeutic strategy in this disease.

Mechanisms of doxorubicin resistance in hepatocellular carcinoma

“…None have yet to demonstrate benefit in clinical trials. In experimental models of HCC, doxorubicin chemosensitization has been achieved with PP2A inhibitors [123], CD13 antibodies [116] or different approaches to inhibit MDR transporters including small molecule inhibitors and antisense constructs [33,124]. Further understanding of the mechanisms responsible for doxorubicin resistance will thus be important to make chemosensitization a routine part of the TACE treatment protocol.…”

Arctigenin inhibits triple-negative breast cancers by targeting CIP2A to reactivate protein phosphatase 2A

“…PP2A functions as a serine/threonine protein phosphatase that regulates several important oncogenic proteins such as Akt, ERK, c-Myc, and p70S6K (7,8). When PP2A is inhibited by CIP2A, PP2A-mediated dephosphorylation of these oncoproteins is blocked, thus promoting anchorage-independent cell growth and in vivo tumor formation.…”

Zinc Finger and X-Linked Factor (ZFX) Binds to Human SET Transcript 2 Promoter and Transactivates SET Expression

“…In breast cancers, SET overexpression is a frequent molecular event associated with shorter overall and disease-free survival of patients [15]. A close correlation between SET expression levels and tumor differentiation was observed in epithelial ovarian cancers [16].…”