CIP2A as a key regulator for AKT phosphorylation has partial impact determining clinical outcome in breast cancer

Luque, Melani; Cristóbal, Ion; Sanz Álvarez, Marta; Santos, Andrea; Zazo, Sandra; Eroles, Pilar; Arpí Llucià, Oriol; Rovira Guerín, Ana; Albanell Mestres, Joan; Madoz-Gúrpide, Juan; García-Foncillas, Jesús; Rojo, Federico

doi:http://dx.doi.org/10.3390/jcm11061610

CIP2A as a key regulator for AKT phosphorylation has partial impact determining clinical outcome in breast cancer

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Luque M, Cristóbal I, Sanz-Álvarez M, Santos A, Zazo S, Eroles P, Arpí O, Rovira A, Albanell J, Madoz-Gúrpide J, García-Foncillas J, Rojo F. CIP2A as a key regulator for AKT phosphorylation has partial impact determining clinical outcome in breast cancer. J Clin Med. 2022 Mar 14;11(6):1610. DOI: 10.3390/jcm11061610

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.