Young Ae Kim

Enhancing mTOR-targeted cancer therapy by preventing mTOR/raptor inhibition-initiated, mTOR/rictor-independent Akt activation

It has been shown that mammalian target of rapamycin (mTOR) inhibitors activate Akt while inhibiting mTOR signaling. However, the underlying mechanisms and the effect of the Akt activation on mTOR-targeted cancer therapy are unclear. The present work focused on addressing the role of mTOR/rictor in mTOR inhibitor-induced Akt activation and the effect of sustained Akt activation on mTOR-targeted cancer therapy. Thus, we have shown that mTOR inhibitors increase Akt phosphorylation through a mechanism independent of mTOR/rictor because the assembly of mTOR/rictor was inhibited by mTOR inhibitors and the silencing of rictor did not abrogate mTOR inhibitor-induced Akt activation. Moreover, Akt activation during mTOR inhibition is tightly associated with development of cell resistance to mTOR inhibitors. Accordingly, cotargeting mTOR and phosphatidylinositol 3-kinase/Akt signaling prevents mTOR inhibition-initiated Akt activation and enhances antitumor effects both in cell cultures and in animal xenograft models, suggesting an effective cancer therapeutic strategy. Collectively, we conclude that inhibition of the mTOR/raptor complex initiates Akt activation independent of mTOR/rictor. Consequently, the sustained Akt activation during mTOR inhibition will counteract the anticancer efficacy of the mTOR inhibitors.

Prognostic Influence of Preoperative Mammographic Breast Density in Operable Invasive Female Breast Cancer

We aimed to investigate the potential of preoperative mammographic breast density (MBD) as a prognostic factor in breast cancer. Data of 969 patients with primary breast cancer were analyzed. We defined low MBD as fatty or fibroglandular breast, and high MBD as heterogeneously dense or extremely dense breast, respectively. The high MBD group demonstrated a superior overall survival rate compared to the low MBD group (p < 0.001). Favorable prognostic effects of high MBD were observed in subgroups aged >50 years (p < 0.001) and with positive hormone receptor (HRc) and negative human epidermal growth factor receptor 2 (HER2) (p < 0.001). The high MBD group had a higher proportion of patients aged ≤50 years (p < 0.001) and patients with body mass index (BMI) ≤25 kg/m2 (p < 0.001), and a higher proportion of patients who received chemotherapy (p < 0.001). MBD was a significant independent prognostic factor by multivariable analysis (hazard ratio, 0.382; 95% confidence interval, 0.206–0.708). The high MBD group was associated with superior overall survival rates. Preoperative MBD was a strong independent prognostic factor in operable primary invasive female breast cancer, especially in patients with age >50 years and the HRc(+)/HER2(−) subtype. Favorable clinicopathologic features, active treatments, and other factors could contribute to this causality.

BCL2 Regulation according to Molecular Subtype of Breast Cancer by Analysis of The Cancer Genome Atlas Database.

Purpose We investigated B-cell lymphoma 2 (BCL2) regulation across DNA, RNA, protein, and methylation status according to molecular subtype of breast cancer using The Cancer Genome Atlas (TCGA) database. Materials and Methods We analyzed clinical and biological data on 1,096 breast cancers from the TCGA database. Biological data included reverse phase protein array (RPPA), mRNA sequencing (mRNA-seq), mRNA microarray, methylation, copy number alteration linear, copy number alteration nonlinear, and mutation data. Results The luminal A and luminal B subtypes showed upregulated expression of RPPA and mRNAseq and hypomethylation compared to the human epidermal growth factor receptor 2 (HER2) and triple-negative subtypes (all p < 0.001). No mutations were found in any subjects. High mRNA-seq and high RPPA were strongly associated with positive estrogen receptor, positive progesterone receptor (all p < 0.001), and negative HER2 (p < 0.001 and p=0.002, respectively). Correlation analysis revealed a strong positive correlation between protein and mRNA levels and a strong negative correlation between methylation and protein and mRNA levels (all p < 0.001). The high BCL2 group showed superior overall survival compared to the low BCL2 group (p=0.006). Conclusion The regulation of BCL2 was mainly associated with methylation across the molecular subtypes of breast cancer, and luminal A and luminal B subtypes showed upregulated expression of BCL2 protein, mRNA, and hypomethylation. Although copy number alteration may have played a minor role, mutation status was not related to BCL2 regulation. Upregulation of BCL2 was associated with superior prognosis than downregulation of BCL2.

Education Level Is a Strong Prognosticator in the Subgroup Aged More Than 50 Years Regardless of the Molecular Subtype of Breast Cancer: A Study Based on the Nationwide Korean Breast Cancer Registry Database

Purpose This study investigated the role of the education level (EL) as a prognostic factor for breast cancer and analyzed the relationship between the EL and various confounding factors. Materials and Methods The data for 64,129 primary breast cancer patients from the Korean Breast Cancer Registry were analyzed. The EL was classified into two groups according to the education period; the high EL group (≥ 12 years) and low EL group (< 12 years). Survival analyses were performed with respect to the overall survival between the two groups. Results A high EL conferred a superior prognosis compared to a low EL in the subgroup aged > 50 years (hazard ratio, 0.626; 95% confidence interval [CI], 0.577 to 0.678) but not in the subgroup aged ≤ 50 years (hazard ratio, 0.941; 95% CI, 0.865 to 1.024). The EL was a significant independent factor in the subgroup aged > 50 years according to multivariate analyses. The high EL group showed more favorable clinicopathologic features and a higher proportion of patients in this group received lumpectomy, radiation therapy, and endocrine therapy. In the high EL group, a higher proportion of patients received chemotherapy in the subgroups with unfavorable clinicopathologic features. The EL was a significant prognosticator across all molecular subtypes of breast cancer. Conclusion The EL is a strong independent prognostic factor for breast cancer in the subgroup aged > 50 years regardless of the molecular subtype, but not in the subgroup aged ≤ 50 years. Favorable clinicopathologic features and active treatments can explain the main causality of the superior prognosis in the high EL group.