Transcriptomic alterations underlying metaplasia into specific metaplastic components in metaplastic breast carcinoma

Abstract

Background Metaplastic breast carcinoma (MpBC) typically consists of carcinoma of no special type (NST) with various metaplastic components. Although previous transcriptomic and proteomic studies have reported subtype-related heterogeneity, the intracase transcriptomic alterations between metaplastic components and paired NST components, which are critical for understanding the pathogenesis underlying the metaplastic processes, remain unclear. Methods Fifty-nine NST components and paired metaplastic components (spindle carcinomatous [SPS], matrix-producing, rhabdoid [RHA], and squamous carcinomatous [SQC] components) were microdissected from specimens obtained from 27 patients with MpBC for gene expression profiling using the NanoString Breast Cancer 360 Panel on a NanoString nCounter FLEX platform. BC360-defined signatures were scored using nSolver software. Results Hierarchical clustering and principal component analysis revealed a heterogeneous gene expression profile (GEP) corresponding to the NST components, but the GEP of metaplastic components exhibited subtype dependence. Compared with the paired NST components, the SPS components demonstrated the upregulation of genes related to stem cells and epithelial–mesenchymal transition and displayed enrichment in claudin-low and macrophage signatures. Despite certain overlaps in the enriched functions and signatures between the RHA and SPS components, the specific differentially expressed genes differed. We observed the RHA-specific upregulation of genes associated with vascular endothelial growth factor signaling. The chondroid matrix-producing components demonstrated the upregulation of hypoxia-related genes and the downregulation of the immune-related MHC2 signature and the TIGIT gene. In the SQC components, TGF-β and genes associated with cell adhesion were upregulated. The differentially expressed genes among metaplastic components in the 22 MpBC cases with one or predominantly one metaplastic component clustered paired NST samples into clusters with correlation with their associated metaplastic types. These genes could be used to separate the 31 metaplastic components according to respective metaplastic types with an accuracy of 74.2%, suggesting that intrinsic signatures of NST may determine paired metaplastic type. Finally, the EMT activity and stem cell traits in the NST components were correlated with specimens displaying lymph node metastasis. Conclusions We presented the distinct transcriptomic alterations underlying metaplasia into specific metaplastic components in MpBCs, which contributes to the understanding of the pathogenesis underlying morphologically distinct metaplasia in MpBCs.

The Importance of Development and Application of Subtyping Models for Breast Cancer on the Same Platform

“…New discoveries regarding the mechanisms [35,36], biomarkers [12], and expression patterns [37] of breast cancer are emerging with the use of intrinsic subtyping tools, speci cally the commonly used PAM50 and AIMS models. However, misclassi cation of intrinsic subtypes could result in decreased research accuracy.…”

Translational Aspects in Metaplastic Breast Carcinoma

“…Huang-Chun Lien and colleagues (2023) categorized transcriptomic alterations underlying metaplasia into specific metaplastic components in MpBCs [56]. They conducted a gene expression profiling analysis on 59 micro-dissected samples using the NanoString BC360 Panel.…”

“…Using the NanoString, Lieu et al ( 2023) demonstrated that cases with prominent spindle components showed an enrichment of macrophage signatures, and the upregulation of genes PD-L2 (also called PDCD1LG2) and B7-H3 that are associated with immune inhibitory pathways [56]. On the other hand, spindle components showed the downregulation of the TIGIT gene, which is related to immune activity.…”

“…For these reasons, a growing list of EMT regulators has been studied and identified, including extracellular and transcription factors, microRNAs, and the microenvironment [56]. Although cancer stem cell properties and EMT have been recognized by many studies, evidence leads to the possibility of there being EMT-independent mechanisms with different EMT inducers [74].…”

A comprehensive overview of metaplastic breast cancer: Features and treatments

“…Metaplastic breast carcinomas have a high degree of genomic instability and display intricate patterns of copy number variations. 11 Compared with TNBC, MpBCs typically harbor significantly more mutations in TP53 (59% vs. 51%), PIK3CA (23% vs. 9%), and other members of the PI3K pathway (41% vs. 18%), 4 present genetic alterations in the Wnt pathway, 11,[15][16][17][18] and demonstrate CDKN2A loss, 11,19 EGFR overexpression and amplification, 11 MYC amplification, 20 TERT promoter hotspot mutations and gene amplification, 10,16,21 the enrichment of angiogenic genes, 22 and changes in genes related to the cell cycle 23 (Table 1). Furthermore, no differences between MpBCs and non-Mp TNBCs in the domains frequently mutated in either TP53 or PIK3CA, showing they have similar genetic alterations.…”