Luminal Stem Cell Determinant SOX9 Controls Lineage Plasticity and Progression in Basal-Like Breast Cancer (ATAC-seq)

Lineage plasticity plays an important role in the development of basal-like breast cancer (BLBC), an aggressive cancer subtype. Although studies suggest BLBC is likely to originate from luminal progenitor cells, it acquires substantial basal cell features and contains a heterogenous collection of cells exhibiting basal, luminal and bipotent phenotypes. Why luminal progenitors are prone to BLBC transformation and what drives luminal-to-basal/bipotent reprogramming remains unclear. Here we show that the transcription factor SOX9 acts as a determinant for ER– luminal stem/progenitor cells (LSPCs). SOX9 controls LSPC activity in part by activating both canonical and non-canonical NF-?B signaling. Inactivation of p53 and Rb in a BLBC mouse tumor model leads to upregulation of SOX9, which drives luminal-to-bipotent reprogramming in vivo. SOX9 deletion inhibits the progression of benign, neoplastic lesions to invasive carcinoma. Furthermore, SOX9 is overexpressed and correlated with shorter relapse-free survival in human BLBC. These data show that ER– LSPC determinant SOX9 acts as a lineage-specific driver for BLBC transformation. Overall design: Mammary glands from three Sox9-GFP; C3(1)/Tag animals were reduced to a single cell suspension. From this suspension luminal Sox9-GFP high and luminal Sox9-GFP low cells were FACS sorted and nuclei was isolated from these populations. The resulting nuclei were exposed to Tn5 and transpoase accesible DNA was sequenced to determine difference in genome accesibility.