A Cancer Proliferation Gene Signature Supervised by Ki-67 Strata Specific to Luminal A, Estrogen Receptor-Positive, and HER2-Negative Ductal Carcinomas

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Youdinghuan Chen

Abstract

Clinically determined Ki-67 is a well-established marker for assessing proliferation potential in breast and other cancers. However, Ki-67 and the recommended thresholds for clinical decision-making vary systematically across breast cancer subtypes. In this study, an analysis of published gene expression data against Ki-67 in ER+/HER2- and Luminal A ductal carcinomas identified 127 of 14,997 protein-coding genes (elastic-net coefficient ≠ 0). The most upregulated genes associated with high Ki-67 are involved in cancer proliferation and were known in breast cancer studies, while the downregulated genes are involved in diverse signaling transduction processes. Application of the identified gene signature to ER+/HER2- and Luminal A ductal carcinomas consistently stratified two independent, population-based breast cancer cohorts. Although the ER+/HER2- clinical and the Luminal A intrinsic subtypes typically show good prognosis, one subpopulation identified by the signature showed an elevated risk of disease recurrence (hazards ratios 1.59 [95% CI 1.02, 2.47] and 3.80 [95% CI 0.83, 17.27] in two independent application cohorts). The present study identifies a proliferation gene signature specific to ER+/HER2- and Luminal A ductal carcinomas, provides biological insight into the more proliferative cancers, and could be a basis for future therapeutic development.

Article Details

How to Cite
CHEN, Youdinghuan. A Cancer Proliferation Gene Signature Supervised by Ki-67 Strata Specific to Luminal A, Estrogen Receptor-Positive, and HER2-Negative Ductal Carcinomas. Medical Research Archives, [S.l.], v. 10, n. 10, oct. 2022. ISSN 2375-1924. Available at: <https://esmed.org/MRA/mra/article/view/3160>. Date accessed: 03 dec. 2022. doi: https://doi.org/10.18103/mra.v10i10.3160.
Section
Research Articles

References

1. Hanahan D. Hallmarks of Cancer: New Dimensions. Cancer Discov. 2022;12(1):31-46. doi:10.1158/2159-8290.CD-21-1059
2. Zhang A, Wang X, Fan C, Mao X. The Role of Ki67 in Evaluating Neoadjuvant Endocrine Therapy of Hormone Receptor-Positive Breast Cancer. Front Endocrinol (Lausanne). 2021;12:687244. doi:10.3389/fendo.2021.687244
3. Nielsen TO, Leung SCY, Rimm DL, et al. Assessment of Ki67 in Breast Cancer: Updated Recommendations From the International Ki67 in Breast Cancer Working Group. JNCI: Journal of the National Cancer Institute. 2021;113(7):808-819. doi:10.1093/jnci/djaa201
4. Zhu X, Chen L, Huang B, et al. The prognostic and predictive potential of Ki-67 in triple-negative breast cancer. Sci Rep. 2020;10(1):225. doi:10.1038/s41598-019-57094-3
5. Cancer Genome Atlas Network. Comprehensive molecular portraits of human breast tumours. Nature. 2012;490(7418):61-70. doi:10.1038/nature11412
6. Curtis C, Shah SP, Chin SF, et al. The genomic and transcriptomic architecture of 2,000 breast tumours reveals novel subgroups. Nature. 2012;486(7403):346-352. doi:10.1038/nature10983
7. Vieira AF, Schmitt F. An Update on Breast Cancer Multigene Prognostic Tests-Emergent Clinical Biomarkers. Front Med (Lausanne). 2018;5:248. doi:10.3389/fmed.2018.00248
8. Wu SZ, Al-Eryani G, Roden DL, et al. A single-cell and spatially resolved atlas of human breast cancers. Nat Genet. 2021;53(9):1334-1347. doi:10.1038/s41588-021-00911-1
9. Friedman J, Hastie T, Tibshirani R. Regularization Paths for Generalized Linear Models via Coordinate Descent. J Stat Softw. 2010;33(1):1-22.
10. Safran M, Rosen N, Twik M, et al. The GeneCards Suite. In: Practical Guide to Life Science Databases. Springer Nature Singapore; 2021:27-56. doi:10.1007/978-981-16-5812-9_2
11. Gao J, Aksoy BA, Dogrusoz U, et al. Integrative Analysis of Complex Cancer Genomics and Clinical Profiles Using the cBioPortal. Sci Signal. 2013;6(269):pl1-pl1. doi:10.1126/scisignal.2004088
12. Piccolella M, Crippa V, Cristofani R, et al. The small heat shock protein B8 (HSPB8) modulates proliferation and migration of breast cancer cells. Oncotarget. 2017;8(6):10400-10415. doi:10.18632/oncotarget.14422
13. Sokol ES, Feng YX, Jin DX, et al. SMARCE1 is required for the invasive progression of in situ cancers. Proc Natl Acad Sci U S A. 2017;114(16):4153-4158. doi:10.1073/pnas.1703931114
14. Carr HS, Zuo Y, Oh W, Frost JA. Regulation of focal adhesion kinase activation, breast cancer cell motility, and amoeboid invasion by the RhoA guanine nucleotide exchange factor Net1. Mol Cell Biol. 2013;33(14):2773-2786. doi:10.1128/MCB.00175-13
15. McCorkle JR, Leonard MK, Kraner SD, et al. The metastasis suppressor NME1 regulates expression of genes linked to metastasis and patient outcome in melanoma and breast carcinoma. Cancer Genomics Proteomics. 11(4):175-194.
16. Litim N, Labrie Y, Desjardins S, et al. Polymorphic variations in the FANCA gene in high-risk non-BRCA1/2 breast cancer individuals from the French Canadian population. Mol Oncol. 2013;7(1):85-100. doi:10.1016/j.molonc.2012.08.002
17. del Valle J, Rofes P, Moreno-Cabrera JM, et al. Exploring the Role of Mutations in Fanconi Anemia Genes in Hereditary Cancer Patients. Cancers (Basel). 2020;12(4). doi:10.3390/cancers12040829
18. Chen Y, Wang Y, Salas LA, et al. Molecular and epigenetic profiles of BRCA1-like hormone-receptor-positive breast tumors identified with development and application of a copy-number-based classifier. Breast Cancer Res. 2019;21(1):14. doi:10.1186/s13058-018-1090-z
19. Moore GM, Powell SN, Higginson DS, Khan AJ. Examining the prevalence of homologous recombination repair defects in ER+ breast cancers. Breast Cancer Res Treat. 2022;192(3):649-653. doi:10.1007/s10549-022-06529-z