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KMID : 1134120220250050387
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Journal of Breast Cancer
2022 Volume.25 No. 5 p.387 ~ p.403
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The Significance of p-AKT1 as a Prognostic Marker and Therapeutic Target in Patients With Hormone Receptor-Positive and Human Epidermal Growth Factor Receptor-2-Positive Early Breast Cancer
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Kim Ji-Yea
Park Chan-Sub
Jang Se-Kyeong
Seol Hye-Sil
Seong Min-Ki
Noh Woo-Chul
Park In-Chul
Kim Hyun-Ah
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Abstract
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Purpose: Phosphorylated AKT1 (p-AKT1) at Ser473 is a functional isoform of AKT and a key component of the PI3K/mTOR/AKT pathway. This study aimed to evaluate the prognostic significance of p-AKT1 (Ser473) based on the molecular subtypes of breast cancer.
Methods: To investigate the prognostic value of p-AKT1 (Ser473), we performed a retrospective chart review of patients with breast cancer. Data on p-AKT1 (Ser473) positivity, hormone receptor (HR) status, human epidermal growth factor receptor 2 (HER2) expression status, and other clinicopathological factors were obtained. Furthermore, the therapeutic effect of blocking p-AKT1 (Ser473) in breast cancer cells was evaluated using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, cell apoptosis assay, apoptosis protein array, and western blot analysis.
Results: A total of 3,044 patients were evaluated, and the median follow-up time was 43 (range: 0?125) months. In patients with HR-positive and HER2-positive disease, the p-AKT1 (Ser473)-positive group had worse disease-free survival (DFS) than the p-AKT1 (Ser473)-negative group (hazard ratio, 1.9; 95% confidence interval, 1.1?3.5; p = 0.024). In the multivariate analysis, p-AKT1 (Ser473) remained a significantly worse prognostic factor in patients with HR-positive/HER2-positive breast cancer (p = 0.03). There was no difference in DFS according to p-AKT1 (Ser473) status among patients with other breast cancer subgroups. In vitro analysis showed that blocking p-AKT1 (Ser473) levels enhanced trastuzumab-induced cell death in HR-positive/HER2-positive and p-AKT1 (Ser473)-positive breast cancer cells.
Conclusion: p-AKT1 (Ser473) is a prognostic marker for poor outcomes in patients with HR-positive/HER2-positive breast cancer and may have a potential value as a therapeutic target.
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KEYWORD
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AKT1 protein, Breast Neoplasms, Disease-Free Survival, Prognosis
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