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Spatial Transcriptomic Profiling Identifies Epithelial Heterogeneity and a Potential Lineage-Associated Marker in Breast Mucinous Cystadenocarcinoma

Yu-Ting Kang1,#, Tzu-Hung Hsiao1,2,3,#, Yidong Chen4,5, I-Tien Chiang1, Li-Wen Lee1, Nam Nhut Phan4, Wei-Yu Chen6,7, Puay Hoon Tan8, Kang-Yu Chang9, Wan-Ching Chen9, Chih-Jung Chen9,10,11,*
1 Department of Medical Research, Taichung Veterans General Hospital, Taichung, Taiwan
2 Department of Public Health, Fu Jen Catholic University, New Taipei City, Taiwan
3 Institute of Genomics and Bioinformatics, National Chung Hsing University, Taichung, Taiwan
4 Greehey Children’s Cancer Research Institute, University of Texas Health San Antonio, San Antonio, TX, USA
5 Department of Population Health Sciences, University of Texas Health San Antonio, San Antonio, TX, USA
6 Department of Pathology, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan
7 Department of Pathology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
8 Luma Medical Centre, Singapore, Singapore
9 Department of Pathology and Laboratory Medicine, Taichung Veterans General Hospital, Taichung, Taiwan
10 School of Medicine, Chung Shan Medical University, Taichung, Taiwan
11 Department of Post-Baccalaureate Medicine, College of Medicine, National Chung Hsing University, Taichung, Taiwan
* Corresponding Author: Chih-Jung Chen. Email: email
# These authors contributed equally to this work
(This article belongs to the Special Issue: Precision Oncology: Targeted Therapies and Tumor Microenvironment)

Oncology Research https://doi.org/10.32604/or.2026.081243

Received 26 February 2026; Accepted 25 August 2026; Published online 01 September 2026

Abstract

Background: Breast mucinous cystadenocarcinoma (BMCA) is an ultra-rare primary breast carcinoma classified within the triple-negative breast cancer (TNBC) molecular category. BMCA poses a significant diagnostic challenge because of its morphologic overlap with invasive mucinous carcinoma of the breast and metastatic mucinous carcinomas from the ovary and pancreas. This study aimed to characterize epithelial transcriptional states and identify molecular features with potential diagnostic utility. Methods: High-resolution spatial transcriptomic profiling was performed on three primary BMCA cases using the 10× Genomics Visium HD platform, with a TNBC specimen included as a transcriptomic reference. IHC analysis was performed using pancreatic and ovarian mucinous carcinomas as comparators. Results: Two transcriptionally distinct epithelial tumour populations were identified within BMCA. One population exhibited increased expression of inflammation-associated genes, including S100 calcium-binding protein A8 (S100A8) and S100 calcium-binding protein A8 (S100A9), and was localized to peripheral epithelial regions with limited histological evidence of immune-cell infiltration, suggesting a tumour-associated inflammatory-like state. Pseudotime analysis of Case 2 suggested that Cancer_2 occupied a relatively less differentiated along the inferred transcriptional-state continuum. Across all three BMCA cases, Mucin5B (MUC5B) expression was consistently detected at both transcriptomic and protein levels. IHC analysis demonstrated markedly higher MUC5B expression in BMCA (H-score: 253.3 ± 80.8) than in pancreatic mucinous cystadenocarcinoma (PMCA; 10.0 ± 10.0) and ovarian mucinous cystadenocarcinoma (OMCA; 11.7 ± 11.5). Conclusions: Spatial transcriptomics identified epithelial heterogeneity within BMCA and highlighted MUC5B as a candidate lineage-associated biomarker. Incorporation of MUC5B immunohistochemistry may aid the differential diagnosis of primary BMCA and metastatic mucinous tumours in routine surgical pathology.

Graphical Abstract

Spatial Transcriptomic Profiling Identifies Epithelial Heterogeneity and a Potential Lineage-Associated Marker in Breast Mucinous Cystadenocarcinoma

Keywords

Breast mucinous cystadenocarcinoma; spatial transcriptomics; epithelial heterogeneity; Mucin-5B; diagnostic pathology
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