Upregulation of CIP2A in estrogen depletion‐resistant breast cancer cells treated with low‐dose everolimus

Nishio, Eiji; Hayashi, Takanori; Akaza, Mao; Hisatomi, Yukiko; Hikichi, Masahiro; Fujii, Takuma; Utsumi, Toshiaki; Harada, Nobuhiro; Shimono, Yohei

doi:10.1002/2211-5463.12956

Cited by 3 publications

(1 citation statement)

References 31 publications

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“…The high relevance of the CIP2A/AKT interplay has been largely reported in the literature. Thus, 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 is an FDA-approved immunosuppressant for multiple sclerosis which has shown promising antitumor effects in many tumor types.…”

Section: Introductionmentioning

confidence: 99%

CIP2A as a Key Regulator for AKT Phosphorylation Has Partial Impact Determining Clinical Outcome in Breast Cancer

Luque

Cristóbal

Sanz-Álvarez

et al. 2022

JCM

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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.

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