Gene Expression Comparison of Pleomorphic Lobular Carcinoma In-Situ with Classical Lobular Carcinoma In-Situ and High-Grade Ductal Carcinoma In-Situ PLCIS gene expression

Matthew Leong (1), Xiaomo Li (2), Kai Ying (3), Helen Nguyen (4), Eric Vail (5), Armando Giuliano (6), Farnaz Dadmanesh (7)
(1) Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA, United States,
(2) Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA, United States,
(3) Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA, United States,
(4) Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, California, USA, United States,
(5) Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, California, USA, United States,
(6) Saul and Joyce Brandman Breast Center, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA, United States,
(7) Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, California, USA, United States
https://doi.org/10.32768/abc.4597261830-058

Article Sidebar

Issue
Vol. 13 No. 2 (2026): Volume 13, Issue 2, May 2026
Submitted
January 16, 2026
Published
April 22, 2026
Keywords:
    breast neoplasms, molecular biology, pathology, molecular, breast carcinoma in situ, gene expression
PDF

Abstract

Background: Pleomorphic lobular carcinoma in situ (PLCIS) shares histologic features with both classical lobular carcinoma in situ (cLCIS) and high-grade ductal carcinoma in-situ (hgDCIS), leading to ambiguity on optimal clinical management. Retrospective gene expression profiling and analysis were used to explore the biological behavior of PLCIS relative to cLCIS and hgDCIS.


Methods: This is a retrospective study. Overall, 16 PLCIS specimens, 10 cLCIS specimens, and 9 hgDCIS cases were included; gene expression using a 725 cancer-related gene expression assay was measured.


Results: PLCIS gene expression profile had greater overlap with cLCIS than hgDCIS. E2F target genes were upregulated in PLCIS compared to cLCIS, while glycolysis genes and interferon-α genes were upregulated in hgDCIS relative to PLCIS.


Conclusion: Although gene set analysis suggests PLICS could have more aggressive behavior than cLCIS, gene expression profiling suggests it has closer biological behavior to cLCIS than to hgDCIS. Long-term clinical outcome studies are still needed to determine prognosis and optimal management.

Full text article

Generated from XML file

References

Pieri A, Harvey J, Bundred N. Pleomorphic lobular carcinoma in situ of the breast: Can the evidence guide practice? World J Clin Oncol. 2014 Aug 10;5(3):546–53. doi:10.5306/wjco.v5.i3.546.

Harrison BT, Nakhlis F, Dillon DA, Soong TR, Garcia EP, Schnitt SJ, et al. Genomic profiling of pleomorphic and florid lobular carcinoma in situ reveals highly recurrent ERBB2 and ERRB3 alterations. Mod Pathol. 2020 Jul;33(7):1287–97. doi:10.1038/s41379-020-0459-6.

Shamir ER, Chen YY, Krings G. Genetic analysis of pleomorphic and florid lobular carcinoma in situ variants: frequent ERBB2/ERBB3 alterations and clonal relationship to classic lobular carcinoma in situ and invasive lobular carcinoma. Mod Pathol. 2020 Jun;33(6):1078–91. doi:10.1038/s41379-019-0449-8.

Blair SL, Emerson DK, Kulkarni S, Hwang ES, Malcarne V, Ollila DW. Breast surgeon’s survey: no consensus for surgical treatment of pleomorphic lobular carcinoma in situ. Breast J. 2013;19(1):116–8. doi:10.1111/tbj.12062.

Robinson MD, McCarthy DJ, Smyth GK. edgeR: a Bioconductor package for differential expression analysis of digital gene expression data. Bioinformatics. 2010 Jan 1;26(1):139–40. doi:10.1093/bioinformatics/btp616.

Liberzon A, Birger C, Thorvaldsdóttir H, Ghandi M, Mesirov JP, Tamayo P. The Molecular Signatures Database (MSigDB) hallmark gene set collection. Cell Syst. 2015 Dec 23;1(6):417–25. doi:10.1016/j.cels.2015.12.004.

Liberzon A, Subramanian A, Pinchback R, Thorvaldsdóttir H, Tamayo P, Mesirov JP. Molecular signatures database (MSigDB) 3.0. Bioinformatics. 2011 Jun 15;27(12):1739–40. doi:10.1093/bioinformatics/btr260.

Mootha VK, Lindgren CM, Eriksson KF, Subramanian A, Sihag S, Lehar J, et al. PGC-1alpha-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes. Nat Genet. 2003 Jul;34(3):267–73. doi:10.1038/ng1180.

Subramanian A, Tamayo P, Mootha VK, Mukherjee S, Ebert BL, Gillette MA, et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci U S A. 2005 Oct 25;102(43):15545–50. doi:10.1073/pnas.0506580102.

Janiszewska M, Primi MC, Izard T. Cell adhesion in cancer: Beyond the migration of single cells. J Biol Chem. 2020 Feb 21;295(8):2495–505. doi:10.1074/jbc.REV119.007759.

Attwooll C, Lazzerini Denchi E, Helin K. The E2F family: specific functions and overlapping interests. EMBO J. 2004 Dec 8;23(24):4709–16. doi:10.1038/sj.emboj.7600481.

Gao Y, Qiao X, Liu Z, Zhang W. The role of E2F2 in cancer progression and its value as a therapeutic target. Front Immunol. 2024;15:1397303. doi:10.3389/fimmu.2024.1397303.

Iglesias-Ara A, Westendorp B. Editorial: The role of E2F transcription factors in cancer. Front Oncol. 2023;13:1355610. doi:10.3389/fonc.2023.1355610.

Nikonezhad B, Lotfian M, Manavi N, Zamani A, Mahdevar M. Insights into the E2F target genes in breast cancer: associations of pathway genes with prognosis and immune cell filtration based on in silico and ex vivo analyses. Cancer Cell Int. 2025 Jun 6;25(1):203. doi:10.1186/s12935-025-03839-2.

Yu L, Chen X, Sun X, Wang L, Chen S. The Glycolytic Switch in Tumors: How Many Players Are Involved? J Cancer. 2017;8(17):3430–40. doi:10.7150/jca.21125.

Zhou D, Duan Z, Li Z, Ge F, Wei R, Kong L. The significance of glycolysis in tumor progression and its relationship with the tumor microenvironment. Front Pharmacol. 2022;13:1091779. doi:10.3389/fphar.2022.1091779.

Du T, Zhu L, Levine KM, Tasdemir N, Lee A V, Vignali DAA, et al. Invasive lobular and ductal breast carcinoma differ in immune response, protein translation efficiency and metabolism. Sci Rep. 2018 May 8;8(1):7205. doi:10.1038/s41598-018-25357-0.

Benguigui M, Cooper TJ, Kalkar P, Schif-Zuck S, Halaban R, Bacchiocchi A, et al. Interferon-stimulated neutrophils as a predictor of immunotherapy response. Cancer Cell. 2024 Feb 12;42(2):253-265.e12. doi:10.1016/j.ccell.2023.12.005.

Shi W, Yao X, Fu Y, Wang Y. Interferon-α and its effects on cancer cell apoptosis. Oncol Lett. 2022 Jul;24(1):235. doi:10.3892/ol.2022.13355.

Yang CH, Murti A, Pfeffer SR, Basu L, Kim JG, Pfeffer LM. IFNalpha/beta promotes cell survival by activating NF-kappa B. Proc Natl Acad Sci USA. 2000 Dec 5;97(25):13631–6. doi:10.1073/pnas.250477397.

Gomez D, Reich NC. Stimulation of primary human endothelial cell proliferation by IFN. J Immunol. 2003 Jun 1;170(11):5373–81. doi:10.4049/jimmunol.170.11.5373.

Martin-Hijano L, Sainz B. The Interactions Between Cancer Stem Cells and the Innate Interferon Signaling Pathway. Front Immunol. 2020;11:526. doi:10.3389/fimmu.2020.00526

Ortega MA, Fraile-Martínez O, Asúnsolo Á, Buján J, García-Honduvilla N, Coca S. Signal Transduction Pathways in Breast Cancer: The Important Role of PI3K/Akt/mTOR. J Oncol. 2020;2020:9258396. doi:10.1155/2020/9258396.

Yousefnia S, Seyed Forootan F, Seyed Forootan S, Nasr Esfahani MH, Gure AO, Ghaedi K. Mechanistic Pathways of Malignancy in Breast Cancer Stem Cells. Front Oncol. 2020;10:452. doi:10.3389/fonc.2020.00452.

Shah V, Nowinski S, Levi D, Shinomiya I, Kebaier Ep Chaabouni N, Gillett C, et al. PIK3CA mutations are common in lobular carcinoma in situ, but are not a biomarker of progression. Breast Cancer Res. 2017 Jan 17;19(1):7. doi:10.1186/s13058-016-0789-y.

Miron A, Varadi M, Carrasco D, Li H, Luongo L, Kim HJ, et al. PIK3CA mutations in in situ and invasive breast carcinomas. Cancer Res. 2010 Jul 15;70(14):5674–8. doi:10.1158/0008-5472.CAN-08-2660

Yee G, Wu R, Ishikawa T, Takabe K. Invasive Lobular Carcinoma Has Higher Immune Response Than Invasive Ductal Carcinoma in Estrogen Receptor-Positive/Human Epidermal Growth Factor Receptor 2-Negative Breast Cancers. World J Oncol. 2025 Oct;16(5):446–56. doi:10.14740/wjon2529.

Tamayo P, Steinhardt G, Liberzon A, Mesirov JP. The limitations of simple gene set enrichment analysis assuming gene independence. Stat Methods Med Res. 2016 Feb;25(1):472–87. doi:10.1177/0962280212460441.

Zhang J, Coombes KR. Sources of variation in false discovery rate estimation include sample size, correlation, and inherent differences between groups. BMC Bioinformatics. 2012;13 Suppl 13(Suppl 13):S1. doi:10.1186/1471-2105-13-S13-S1.

Authors

Matthew Leong
Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA
https://orcid.org/0009-0007-2655-297X
Xiaomo Li
Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA
https://orcid.org/0000-0003-0510-7811
Kai Ying
Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA
https://orcid.org/0009-0008-0912-4006
Helen Nguyen
Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, California, USA
Eric Vail
Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, California, USA
Armando Giuliano
Saul and Joyce Brandman Breast Center, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA
Farnaz Dadmanesh
Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, California, USA
Farnaz.Dadmanesh@cshs.org (Primary Contact)
1.
Leong M, Li X, Ying K, Nguyen H, Vail E, Giuliano A, et al. Gene Expression Comparison of Pleomorphic Lobular Carcinoma In-Situ with Classical Lobular Carcinoma In-Situ and High-Grade Ductal Carcinoma In-Situ: PLCIS gene expression. Arch Breast Cancer [Internet]. 2026 Apr. 22 [cited 2026 Apr. 22];13(2):243-9. Available from: https://www.archbreastcancer.com/index.php/abc/article/view/1274
Download Citation
Endnote/Zotero/Mendeley (RIS)

Copyright (c) 2026 Archives of Breast Cancer

Creative Commons License

This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.

Copyright©. This is an open-access article distributed under the terms of the Creative Commons Attribution-Non-Commercial 4.0 International License, which permits copy and redistribution of the material in any medium or format or adapt, remix, transform, and build upon the material for any purpose, except for commercial purposes.

Article Details