Heditsian, D. | bioRxiv Science

bioRxiv2026

Genome Organizer SATB1 selectively activates a defined subset of EMT genes driving metastatic breast cancer

SATB1 reshapes chromatin architecture and transcriptional programs to promote breast cancer metastasis. However, its key downstream effectors remain incompletely defined. Here, we aimed to identify actionable drivers of invasion by focusing on epithelial-mesenchymal transition (EMT) genes. We identified 98 of 300 curated EMT-promoting genes as direct SATB1 targets in human breast epithelial cells (MCF10A-1) rendered tumorigenic with metastatic traits by SATB1 transduction, using Global Run-On Sequencing (GRO-seq) to measure nascent transcripts. These SATB1-activated EMT genes regulate extracellular matrix remodeling, hypoxia-responsive transcriptional programs, and tumor microenvironmental programs linking angiogenesis and immune evasion, collectively enhancing metastatic competence. Triple-negative breast cancer (TNBC) is a heterogeneous disease characterized by frequent metastasis and chemoresistance. Among the four TNBC molecular subtypes, the 98 SATB1-regulated EMT genes were significantly enriched and activated in the Basal-like 2 (BL2) subtype (Fishers exact test: p = 4.53e-9), which is associated with aggressive behavior, poorer clinical outcomes, and reduced treatment responsiveness. In contrast, SATB1-independent EMT genes showed no enrichment in BL2, indicating selective regulation of EMT genes by SATB1. We further analyzed nascent transcripts induced by the environmental carcinogen benzo[a]pyrene (B[a]P), a known breast carcinogen. Half of the 72 EMT genes activated after short-term B[a]P exposure overlapped with SATB1-dependent EMT genes, indicating that two distinct etiologies, SATB1 and B[a]P, converge on a largely shared network of invasion-promoting genes. These results show that EMT genes are not globally or randomly activated in breast cancer but are selectively activated, defining an EMT gene network associated with metastatic risk. This gene signature may serve as a prognostic marker pending further validation.

cancer biology↗

bioRxiv2024

Gut and oral microbial community characterization from women with breast cancer, women with ductal carcinoma in situ, and healthy women reveals differences in gut but not oral microbiota

This study characterized and compared the fecal and oral microbiota from women with early-stage breast cancer (BC), women with ductal carcinoma in situ (DCIS), and healthy women. Fecal and oral samples were collected from newly diagnosed patients prior to any therapy and characterized using 16S rRNA sequencing. Measures of gut microbial alpha diversity were significantly lower in the BC versus healthy cohort. Beta diversity differed significantly between the BC or DCIS and healthy groups and several differentially abundant taxa were identified. Clustering (non-negative matrix factorization) of the gut microbiota identified 5 bacterial guilds dominated by either Prevotella, Enterobacteriaceae, Akkermansia, Clostridiales, or Bacteroides. The Bacteroides and Enterobacteriaceae guilds were significantly more abundant in the BC cohort compared to healthy controls whereas the Clostridiales guild was more abundant in the healthy group. Finally, prediction of functional pathways identified 23 pathways that differed between the BC and healthy gut microbiota including lipopolysaccharide biosynthesis, glycan biosynthesis and metabolism, lipid metabolism, and sphingolipid metabolism. In contrast to the gut microbiomes, there were no significant differences in alpha or beta diversity in the oral microbiomes and very few differentially abundant taxa were observed. NMF analysis of the oral microbiota samples identified 7 guilds dominated by Veillonella, Prevotella, Gemellaceae, Haemophilus, Neisseria, Propionibacterium, and Streptococcus, however, none of these guilds were differentially associated with the different cohorts. Our results suggest that alterations in the gut microbiota, but not oral microbiota, may provide the basis for interventions targeting the gut microbiome to improve treatment outcomes and long-term prognosis. IMPORTANCEEmerging evidence suggests that the gut microbiota may play a role in breast cancer. Few studies have evaluated both the gut and oral microbiomes in women with breast cancer (BC) and none have characterized these microbiomes in women with ductal carcinoma in situ (DCIS). We surveyed the gut and oral microbiomes from women with BC or DCIS and healthy women and identified compositional and functional features of the gut microbiota that differed between these cohorts. In contrast, very few differential features were identified in the oral microbiota. These findings suggest that the oral microbiome is unlikely to be an effective risk marker for DCIS or breast cancer compared to the gut microbiome. Understanding the role of gut bacteria in BC and DCIS may open up new opportunities for the development of novel markers for early detection (or markers of susceptibility) as well as new strategies for prevention and/or treatment.

microbiology↗