Luque Melani, Cristóbal Ion, Sanz-Álvarez Marta, Santos Andrea, Zazo Sandra, Eroles Pilar, Arpí Oriol, Rovira Ana, Albanell Joan, Madoz-Gúrpide Juan, García-Foncillas Jesús, Rojo Federico
Pathology Department, IIS-Fundación Jiménez Diaz-UAM, 28040 Madrid, Spain.
Cancer Unit for Research on Novel Therapeutic Targets, Oncohealth Institute, ISS-FJD-UAM, 28040 Madrid, Spain.
J Clin Med. 2022 Mar 14;11(6):1610. doi: 10.3390/jcm11061610.
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.
癌蛋白CIP2A具有调节多种肿瘤类型中AKT磷酸化（p-AKT）状态的能力，已被描述可诱导乳腺癌进展和耐药。然而，CIP2A/AKT相互作用在乳腺癌中的临床和治疗相关性仍有待充分阐明。在此，我们发现220例病例中有80例（36.4%）p-AKT水平较高，这与雌激素受体阴性表达（p = 0.049）和CIP2A过表达（p < 0.001）相关。有趣的是，p-AKT显著缩短了总生存期（p = 0.002）和无进展生存期（p = 0.003），多变量分析显示其具有不依赖CIP2A的预后价值。此外，在按分子亚型对我们的系列进行分层后，其临床相关性在三阴性和HER2阳性亚组中得到进一步证实。在功能上，我们在体外证实了CIP2A作为乳腺癌细胞系中p-AKT水平调节因子的作用，并且CIP2A/AKT轴的重要性在体内也得到了验证。最后，在体外分析中，p-AKT对阿霉素反应的预测价值也高于CIP2A。总之，我们的研究结果表明CIP2A过表达是AKT磷酸化的关键促成事件，并突出了CIP2A/AKT轴作为乳腺癌中有前景的治疗靶点。然而，我们的观察结果突出了在未改变CIP2A表达的乳腺癌亚组中存在调节AKT信号传导的替代机制，这决定了其作为该疾病不良预后标志物的独立价值。
