EIF3B expression relates to poor breast cancer prognosis and a palbociclib-response metric in basal-group cell lines
Introduction: The relationship of EIF3B to breast cancer prognosis, cell-cycle regulation, and palbociclib response remains incompletely defined.
Objective: To examine EIF3B associations and evaluate the effects of its silencing with palbociclib treatment.
Methods: The Cancer Genome Atlas-Breast Invasive Carcinoma project and public protein and drug-response datasets were analyzed. EIF3B was silenced in MDA-MB-468 and MDA-MB-231 cells for cell-cycle profiling, retinoblastoma protein measurements, and Cell Counting Kit-8 (CCK-8) assays. RNA sequencing used MDA-MB-468 cells with three independent biological samples per group.
Results: EIF3B expression was higher in breast tumors and highest in the basal-like subtype. High expression was associated with shorter overall survival and progression-free interval in median-split analyses; the clinicopathologic multivariable model retained an overall-survival association. Continuous-expression and age/Prediction Analysis of Microarray 50-adjusted, stage-stratified analyses were nonsignificant. An exploratory Genomics of Drug Sensitivity in Cancer 1 comparison of 27 breast cancer cell lines showed a higher palbociclib natural logarithm of half maximal inhibitory concentration in micromolar units in the recorded High group (n = 14) than in the Low group (n = 13; difference, 0.979; 95% confidence interval, 0.061–1.896; p = 0.0376). The continuous 46-cell-line analysis was nonsignificant. Silencing altered cell-cycle transcriptional programs in MDA-MB-468 and phase distributions in both models. Combined silencing and palbociclib treatment produced the lowest mean CCK-8 viability in both models.
Conclusion: High EIF3B expression was associated with unfavorable survival and reduced palbociclib sensitivity in the grouped cell-line analysis. In MDA-MB-468 cells, EIF3B silencing reduced the S-phase fraction, increased the G0/G1 and G2/M fractions, and enhanced palbociclib-mediated growth inhibition. EIF3B is a candidate prognostic factor associated with palbociclib response.
- Siegel RL, Giaquinto AN, Jemal A. Cancer statistics, 2024. CA Cancer J Clin. 2024;74(1):12-49. doi: 10.3322/caac.21820
- Cancer Genome Atlas Network. Comprehensive molecular portraits of human breast tumours. Nature. 2012;490(7418):61-70. doi: 10.1038/nature11412
- Parker JS, Mullins M, Cheang MCU, et al. Supervised risk predictor of breast cancer based on intrinsic subtypes. J Clin Oncol. 2009;27(8):1160-1167. doi: 10.1200/JCO.2008.18.1370
- Huppert LA, Wolf D, Yau C, et al. Pathologic complete response (pCR) rates for patients with HR+/HER2- high-risk, early-stage breast cancer (EBC) by clinical and molecular features in the phase II I-SPY2 clinical trial. Ann Oncol. 2025;36(2):172-184. doi: 10.1016/j.annonc.2024.10.018
- Ortmann O, Blohmer JU, Sibert NT, et al. Current clinical practice and outcome of neoadjuvant chemotherapy for early breast cancer: analysis of individual data from 94,638 patients treated in 55 breast cancer centers. J Cancer Res Clin Oncol. 2023;149(3):1195-1209. doi: 10.1007/s00432-022-03938-x
- von Minckwitz G, Untch M, Blohmer JU, et al. Definition and impact of pathologic complete response on prognosis after neoadjuvant chemotherapy in various intrinsic breast cancer subtypes. J Clin Oncol. 2012;30(15):1796-1804. doi: 10.1200/JCO.2011.38.8595
- Lee ASY, Kranzusch PJ, Cate JHD. eIF3 targets cell-proliferation messenger RNAs for translational activation or repression. Nature. 2015;522(7554):111-114. doi: 10.1038/nature14267
- Gomes-Duarte A, Lacerda R, Menezes J, Romao L. eIF3: a factor for human health and disease. RNA Biol. 2018;15(1):26-34. doi: 10.1080/15476286.2017.1391437
- Yin Y, Long J, Sun Y, et al. The function and clinical significance of eIF3 in cancer. Gene. 2018;673:130-133. doi: 10.1016/j.gene.2018.06.034
- Wang L, Wen X, Luan F, et al. EIF3B is associated with poor outcomes in gastric cancer patients and promotes cancer progression via the PI3K/AKT/mTOR signaling pathway. Cancer Manag Res. 2019;11:7877-7891. doi: 10.2147/CMAR.S207834
- Zhu H, Shan Y, Ge K, Lu J, Kong W, Jia C. EIF3B promotes cancer progression in pancreatic cancer. Scand J Gastroenterol. 2021;56(3):281-288. doi: 10.1080/00365521.2020.1868566
- Song S, Liu J, Zhang M, et al. Eukaryotic translation initiation factor 3 subunit B could serve as a potential prognostic predictor for breast cancer. Bioengineered. 2022;13(2):2762-2776. doi: 10.1080/21655979.2021.2017567
- Li Y, Zhao J, Yuan Z, et al. Eukaryotic initiation factor 3b regulates the development and progression of breast cancer. Am J Cancer Res. 2023;13(5):2188-2200.
- Flaherty KT, LoRusso PM, DeMichele A, et al. Phase I, dose-escalation trial of the oral cyclin-dependent kinase 4/6 inhibitor PD 0332991, administered using a 21-day schedule in patients with advanced cancer. Clin Cancer Res. 2012;18(2):568-576. doi: 10.1158/1078-0432.CCR-11-0509
- Tamura K, Mukai H, Naito Y, et al. Phase I study of palbociclib, a cyclin-dependent kinase 4/6 inhibitor, in Japanese patients. Cancer Sci. 2016;107(6):755-763. doi: 10.1111/cas.12932
- Groenland SL, Martinez-Chavez A, van Dongen MGJ, et al. Clinical pharmacokinetics and pharmacodynamics of the cyclin-dependent kinase 4 and 6 inhibitors palbociclib, ribociclib, and abemaciclib. Clin Pharmacokinet. 2020;59(12):1501-1520. doi: 10.1007/s40262-020-00930-x
- Mukai H, Shimizu C, Masuda N, et al. Palbociclib in combination with letrozole in patients with estrogen receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer: PALOMA-2 subgroup analysis of Japanese patients. Int J Clin Oncol. 2019;24(3):274-287. doi: 10.1007/s10147-018-1353-9
- Morrison L, Loibl S, Turner NC. The CDK4/6 inhibitor revolution - a game-changing era for breast cancer treatment. Nat Rev Clin Oncol. 2024;21(2):89-105. doi: 10.1038/s41571-023-00840-4
- Goel S, Bergholz JS, Zhao JJ. Targeting CDK4 and CDK6 in cancer. Nat Rev Cancer. 2022;22(6):356-372. doi: 10.1038/s41568-022-00456-3
- Pandey K, An HJ, Kim SK, et al. Molecular mechanisms of resistance to CDK4/6 inhibitors in breast cancer: a review. Int J Cancer. 2019;145(5):1179-1188. doi: 10.1002/ijc.32020
- Watt AC, Goel S. Cellular mechanisms underlying response and resistance to CDK4/6 inhibitors in the treatment of hormone receptor-positive breast cancer. Breast Cancer Res. 2022;24(1):17. doi: 10.1186/s13058-022-01510-6
- Liu CY, Lau KY, Hsu CC, et al. Combination of palbociclib with enzalutamide shows in vitro activity in RB proficient and androgen receptor positive triple negative breast cancer cells. PLoS One. 2017;12(12):e0189007. doi: 10.1371/journal.pone.0189007
- Yamamoto T, Kanaya N, Somlo G, Chen S. Synergistic anti-cancer activity of CDK4/6 inhibitor palbociclib and dual mTOR kinase inhibitor MLN0128 in pRb-expressing ER-negative breast cancer. Breast Cancer Res Treat. 2019;174(3):615-625. doi: 10.1007/s10549-018-05104-9
- Uhlén M, Fagerberg L, Hallström BM, et al. Tissue-based map of the human proteome. Science. 2015;347(6220):1260419. doi: 10.1126/science.1260419
- Newman AM, Liu CL, Green MR, et al. Robust enumeration of cell subsets from tissue expression profiles. Nat Methods. 2015;12(5):453-457. doi: 10.1038/nmeth.3337
- Chen B, Khodadoust MS, Liu CL, Newman AM, Alizadeh AA. Profiling tumor infiltrating immune cells with CIBERSORT. In: Methods in Molecular Biology. Vol 1711. New York, NY: Springer; 2018:243-259. doi: 10.1007/978-1-4939-7493-1_12
- Hänzelmann S, Castelo R, Guinney J. GSVA: gene set variation analysis for microarray and RNA-seq data. BMC Bioinformatics. 2013;14:7. doi: 10.1186/1471-2105-14-7
- Bindea G, Mlecnik B, Tosolini M, et al. Spatiotemporal dynamics of intratumoral immune cells reveal the immune landscape in human cancer. Immunity. 2013;39(4):782-795. doi: 10.1016/j.immuni.2013.10.003
- Qiu Z, Deng C, Zhou F, et al. Ferroptosis heterogeneity within the tumor microenvironment revealed a genetic blueprint of breast cancer. Environ Toxicol. 2024;39(5):2741-2752. doi: 10.1002/tox.24142
- Qiu Z, Lin Y, Chen S, et al. NUP62 promotes breast cancer progression and inhibits ferroptosis by stabilizing NRF2 in a KEAP1-dependent way. iScience. 2026;29(5):115484. doi: 10.1016/j.isci.2026.115484