Background: The 20-year breast cancer-specific mortality rate following ductal carcinoma in situ (DCIS) diagnosis is approximately 3.3%. The current radiation and anti-hormonal therapy have not reduced mortality associated with DCIS, which is quite intriguing. Additionally, studies have shown that HER2 could be a potential biomarker of DCIS with a risk of regional and distant metastasis. Approach: Patient DCIS and DCIS with associated IDC were subjected to single cell (sc)-ATAC/sc-RNA sequencing and spatial transcriptomics. Results: The analysis of scATAC/RNA sequencing of epithelial cells from patients with DCIS and DCIS with associated IDC using CytoTRAE (stemness algorithm) as defined by Gulati et al., revealed that two clusters had the highest stemness scores. These two clusters also exhibited high expression of FOXA1, and a strong correlation was observed between stemness score and FOXA1 expression, particularly in HER2-3+ DCIS/IDC samples compared to HER2-3+ pure DCIS, luminal or TNBC. We also found that the open chromatin regions in the stemness clusters were highly enriched for FOXA1 binding motifs, particularly in HER2-3+ DCIS/IDC samples. Additionally, we performed spatial transcriptomics on sixteen patient DCIS samples. As expected, the CytoTRACE analysis indicated that luminal HR+ epithelial cells in DCIS/IDC HER2-3+ samples exhibited the highest overall level of stemness. FOXA1 was identified as one of the top 10 genes associated with stemness. Ligand receptor (LR) interaction analysis identified the highest dissimilar LR pairs was CEACAM6-EGFR. CEACAM6 was upregulated on luminal HR+ cells with the highest stemness scores and interacted with EGFR expressed by luminal secretory, B cells, T cells, myeloid, mast cells vascular and lymphatic cells. Conclusion: Our data support the hypothesis that targeting the activity of FOXA1 (LSD1 inhibitor) can inhibit the function of stem-like cells and prevent metastatic or invasive progression of human DCIS.