Abstract
Together with its reported ability to modulate AKT phosphorylation (p-AKT) status in several tumor types, the oncoprotein CIP2A has been described to induce breast cancer progression and drug resistance. However, the clinical and therapeutic relevance of the CIP2A/AKT interplay in breast cancer remains to be fully clarified. Here, we found high p-AKT levels in 80 out of 220 cases (36.4%), which were associated with negative estrogen receptor expression (p = 0.049) and CIP2A overexpression (p < 0.001). Interestingly, p-AKT determined substantially shorter overall (p = 0.002) and progression-free survival (p = 0.003), and multivariate analyses showed its CIP2A-independent prognostic value. Moreover, its clinical relevance was further confirmed in the triple negative and HER2-positive subgroups after stratifying our series by molecular subtype. Functionally, we confirmed in vitro the role of CIP2A as a regulator of p-AKT levels in breast cancer cell lines, and the importance of the CIP2A/AKT axis was also validated in vivo. Finally, p-AKT also showed a higher predictive value of response to doxorubicin than CIP2A in ex vivo analyses. In conclusion, our findings suggest that CIP2A overexpression is a key contributing event to AKT phosphorylation and highlights the CIP2A/AKT axis as a promising therapeutic target in breast cancer. However, our observations highlight the existence of alternative mechanisms that regulate AKT signaling in a subgroup of breast tumors without altered CIP2A expression that determines its independent value as a marker of poor outcome in this disease.
Highlights
Breast cancer is a very heterogeneous disease at the molecular level and it represents the most frequently diagnosed cancer in women worldwide [1,2]
It has been progressively reported that CIP2A overexpression plays an oncogenic role and predicts adverse outcomes in a wide variety of human cancers including breast cancer [47,48]
We aimed here to study the functional and clinical value of the CIP2A/p-AKT interplay, analyzing the contribution of CIP2A and p-AKT separately. We investigated both p-AKT and CIP2A levels in a cohort of 220 breast cancer patients, observing that high p-AKT levels strongly correlated with high CIP2A expression and that both markers were predictive of poor outcome
Summary
Breast cancer is a very heterogeneous disease at the molecular level and it represents the most frequently diagnosed cancer in women worldwide [1,2]. CIP2A have been described to regulate AKT activation in several tumor cell lines including breast cancer [12,13]. CIP2A has been reported to regulate proliferation and apoptosis [17], invasion [18], cell cycle progression [19], and it has been associated with human breast cancer aggressiveness [20]. CIP2A overexpression hasbeen reported to predict poor outcome in breast cancer [12,25], with a special relevance in the TN subtype [26,27]. The high relevance of the CIP2A/AKT interplay has been largely reported in the literature Several compounds such as cucurbitacin B [29] and everolimus [30] in the ER-positive subtype, together with lapatinib [31], arctigenin [32], and the erlotinib derivative TD52 [33] in the TN subtype, have demonstrated to exert their antitumor properties in breast cancer, downregulating both CIP2A and p-AKT. FTY720 has been reported to activate the tumor suppressor PP2A due to its mechanism of action based on CIP2A downregulation and SET blocking, both potent PP2A endogenous inhibitors [34–36]
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