Unveiling Heterogeneity and Prognostic Markers in Ductal Breast Cancer Through Single-cell RNA-seq

Overview

Journal Cancer Cell Int

Publisher Biomed Central

Date 2024 Jul 27

PMID 39068476

Authors

Jianxun Hou

Wei Liu

Meihong Yan

Yanlv Ren

Cheng Qian

Yingqiang Fu

Hongbin Wang

Zhigao Li

Affiliations

Soon will be listed here.

Abstract

Background: Breast cancer (BC) is a heterogeneous disease, with the ductal subtype exhibiting significant cellular diversity that influences prognosis and response to treatment. Single-cell RNA sequencing data from the GEO database were utilized in this study to investigate the underlying mechanisms of cellular heterogeneity and to identify potential prognostic markers and therapeutic targets.

Methods: Bioinformatics analysis was conducted using R packages to analyze the single-cell sequencing data. The presence of highly variable genes and differences in malignant potency within the same BC samples were examined. Differential gene expression and biological function between Type 1 and Type 2 ductal epithelial cells were identified. Lasso regression and Cox proportional hazards regression analyses were employed to identify genes associated with patient prognosis. Experimental validation was performed in vitro and in vivo to confirm the functional relevance of the identified genes.

Results: The analysis revealed notable heterogeneity among BC cells, with the presence of highly variable genes and differences in malignant behavior within the same samples. Significant disparities in gene expression and biological function were identified between Type 1 and Type 2 ductal epithelial cells. Through regression analyses, CYP24A1 and TFPI2 were identified as pivotal genes associated with patient prognosis. Kaplan-Meier curves demonstrated their prognostic significance, and experimental validation confirmed their inhibitory effects on malignant behaviors of ductal BC cells.

Conclusion: This study highlights the cellular heterogeneity in ductal subtype breast cancer and delineates the differential gene expressions and biological functions between Type 1 and Type 2 ductal epithelial cells. The genes CYP24A1 and TFPI2 emerged as promising prognostic markers and therapeutic targets, exhibiting inhibitory effects on BC cell malignancy in vitro and in vivo. These findings offer the potential for improved BC management and the development of targeted treatment strategies.

Citing Articles

Single-cell profiling transcriptomic reveals cellular heterogeneity and cellular crosstalk in breast cancer lymphatic node, bone, and brain metastases.

Zhu L, Liu M, Shang Y, Cheng J, Zhao H, Zhang J Sci Rep. 2025; 15(1):2217.

PMID: 39820531 PMC: 11739685. DOI: 10.1038/s41598-025-85531-z.

Thiazolidinedione derivatives in cancer therapy: exploring novel mechanisms, therapeutic potentials, and future horizons in oncology.

Ranjan G, Ranjan S, Sunita P, Pattanayak S Naunyn Schmiedebergs Arch Pharmacol. 2024; .

PMID: 39621087 DOI: 10.1007/s00210-024-03661-z.

The development of the occurrence and metastasis of breast cancer by single-cell sequencing.

Chen M, Feng M, Lei H, Mo D, Ren S, Yang D Cancer Cell Int. 2024; 24(1):349.

PMID: 39462368 PMC: 11515250. DOI: 10.1186/s12935-024-03531-x.

Single-Cell RNA-Sequencing: Opening New Horizons for Breast Cancer Research.

Xiang L, Rao J, Yuan J, Xie T, Yan H Int J Mol Sci. 2024; 25(17).

PMID: 39273429 PMC: 11395021. DOI: 10.3390/ijms25179482.

References

Ereful N, Lalusin A, Laurena A . RNA-Seq Reveals Differentially Expressed Genes Associated with High Fiber Quality in Abaca ( Nee). Genes (Basel). 2022; 13(3). PMC: 8953247. DOI: 10.3390/genes13030519. View

Saponaro F, Saba A, Zucchi R . An Update on Vitamin D Metabolism. Int J Mol Sci. 2020; 21(18). PMC: 7554947. DOI: 10.3390/ijms21186573. View

Yu G, Wang L, Han Y, He Q . clusterProfiler: an R package for comparing biological themes among gene clusters. OMICS. 2012; 16(5):284-7. PMC: 3339379. DOI: 10.1089/omi.2011.0118. View

Cai J, Liu P, Huang H, Li Y, Ma S, Zhou H . Combination of anti-PD-1 antibody with P-GEMOX as a potentially effective immunochemotherapy for advanced natural killer/T cell lymphoma. Signal Transduct Target Ther. 2020; 5(1):289. PMC: 7772337. DOI: 10.1038/s41392-020-00331-3. View

Sadhu S, Wang S, Dachineni R, Averineni R, Seefeldt T, Xie J . In Vitro and In Vivo Antimetastatic Effect of Glutathione Disulfide Liposomes. Cancer Growth Metastasis. 2017; 10:1179064417695255. PMC: 5345945. DOI: 10.1177/1179064417695255. View

Ma P, Amemiya H, He L, Gandhi S, Nicol R, Bhattacharyya R . Bacterial droplet-based single-cell RNA-seq reveals antibiotic-associated heterogeneous cellular states. Cell. 2023; 186(4):877-891.e14. PMC: 10014032. DOI: 10.1016/j.cell.2023.01.002. View

Munz C . Tumor Microenvironment Conditioning by Abortive Lytic Replication of Oncogenic γ-Herpesviruses. Adv Exp Med Biol. 2020; 1225:127-135. DOI: 10.1007/978-3-030-35727-6_9. View

Garrett B, Riou M . A rapid evidence assessment of recent therapeutic touch research. Nurs Open. 2021; 8(5):2318-2330. PMC: 8363410. DOI: 10.1002/nop2.841. View

Styles M, Alsharshani D, Samara M, Alsharshani M, Khattab A, Qoronfleh M . Risk factors, diagnosis, prognosis and treatment of autism. Front Biosci (Landmark Ed). 2020; 25(9):1682-1717. DOI: 10.2741/4873. View

10.

Grimm L, Rahbar H, Abdelmalak M, Hall A, Ryser M . Ductal Carcinoma in Situ: State-of-the-Art Review. Radiology. 2021; 302(2):246-255. PMC: 8805655. DOI: 10.1148/radiol.211839. View

11.

Lin E, Lin C, Lane H . Precision Psychiatry Applications with Pharmacogenomics: Artificial Intelligence and Machine Learning Approaches. Int J Mol Sci. 2020; 21(3). PMC: 7037937. DOI: 10.3390/ijms21030969. View

12.

Tutt A, Garber J, Kaufman B, Viale G, Fumagalli D, Rastogi P . Adjuvant Olaparib for Patients with - or -Mutated Breast Cancer. N Engl J Med. 2021; 384(25):2394-2405. PMC: 9126186. DOI: 10.1056/NEJMoa2105215. View

13.

Torres D, Normando D . Biostatistics: essential concepts for the clinician. Dental Press J Orthod. 2021; 26(1):e21spe1. PMC: 8018753. DOI: 10.1590/2177-6709.26.1.E21SPE1. View

14.

Aran D, Looney A, Liu L, Wu E, Fong V, Hsu A . Reference-based analysis of lung single-cell sequencing reveals a transitional profibrotic macrophage. Nat Immunol. 2019; 20(2):163-172. PMC: 6340744. DOI: 10.1038/s41590-018-0276-y. View

15.

Youngblood M, Gunel M . Molecular genetics of meningiomas. Handb Clin Neurol. 2020; 169:101-119. DOI: 10.1016/B978-0-12-804280-9.00006-8. View

16.

Morch C, Atsu S, Cai W, Li X, Madathil S, Liu X . Artificial Intelligence and Ethics in Dentistry: A Scoping Review. J Dent Res. 2021; 100(13):1452-1460. DOI: 10.1177/00220345211013808. View

17.

Clark T . Journal of molecular modeling conversations. J Mol Model. 2022; 28(9):271. PMC: 9411243. DOI: 10.1007/s00894-022-05191-y. View

18.

McCart Reed A, Kalinowski L, Simpson P, Lakhani S . Invasive lobular carcinoma of the breast: the increasing importance of this special subtype. Breast Cancer Res. 2021; 23(1):6. PMC: 7792208. DOI: 10.1186/s13058-020-01384-6. View

19.

Butler A, Hoffman P, Smibert P, Papalexi E, Satija R . Integrating single-cell transcriptomic data across different conditions, technologies, and species. Nat Biotechnol. 2018; 36(5):411-420. PMC: 6700744. DOI: 10.1038/nbt.4096. View

20.

Zhou T, Wang T, Garcia J . Genes influenced by the non-muscle isoform of Myosin light chain kinase impact human cancer prognosis. PLoS One. 2014; 9(4):e94325. PMC: 3979809. DOI: 10.1371/journal.pone.0094325. View