转录组分析揭示浸润性乳腺癌中肌上皮细胞的重编程

INTRODUCTION: Myoepithelial cells (MECs) in ductal carcinoma in situ (DCIS), although morphologically similar to normal MECs, exhibit distinct functional properties that promote progression to invasive breast cancer. To investigate MEC alterations in invasive disease (IDC), we performed a transcriptomic comparison of MECs within IDC and adjacent normal breast tissues from the same patient specimens. METHODS: Breast cancer tissue specimens were obtained from HCA Houston Healthcare Southeast (Pasadena, TX). MEC presence within invasive ductal carcinoma (IDC) was validated by alpha-smooth muscle actin (alphaSMA) staining and confirmed by a pathologist. Seven untreated, loco-regional invasive breast carcinoma FFPE blocks were sent to BioChain Institute for spatial transcriptomic profiling using the GeoMx Digital Spatial Profiler (DSP, NanoString). H&E staining was used to identify suitable regions, and a 3 mm core tissue microarray (TMA) was constructed using both tumor and adjacent normal tissues. MEC transcriptomes were profiled on 5 μm TMA sections, with ROIs selected based on alphaSMA, PanCK, and Syto13 staining to distinguish MECs from stroma, and indexing oligonucleotides were collected for sequencing. Libraries were prepared and sequenced on an Illumina NextSeq2000 platform. Bioinformatics analyses were conducted in R by The Bioinformatics CRO using EdgeR, fgsea, and clusterProfiler, with normalization, differential expression, gene set enrichment analysis and functional pathway analysis revealing molecular distinctions between tumor-associated and adjacent normal MECs. RESULTS : Our analysis revealed profound molecular reprogramming across three principal domains: extracellular matrix interactions, epithelial-mesenchymal transition, and cellular signaling. Key molecular alterations included (1) widespread upregulation of 17 distinct collagen isoform genes, indicating active stromal remodeling; (2) increased expression of matrix metalloproteinases ( MMP2 , MMP9 , MMP11 , and MMP14 ), suggesting compromised basement membrane integrity; and (3) significant dysregulation of epithelial markers ( KRT5 , KRT7 , and KRT14 ), characteristic of a transitional phenotype resembling cancer-associated fibroblasts. Additional findings included elevated expression of pro-tumorigenic genes ( SPARC , POSTN ) and integrin subunits, alongside alterations in growth factor signaling pathways. These findings, although limited by the sample size and the transcriptomic approach, align with previously reported molecular alterations associated with myoepithelial reprogramming in DCIS-associated MECs. CONCLUSION: This comprehensive transcriptomic analysis demonstrates significant molecular plasticity of myoepithelial cells within the IDC microenvironment, consistent with a phenotypic transition from tumor-suppressive to tumor-promoting function.