Luminal Stem Cell Determinant SOX9 Controls Lineage Plasticity and Progression in Basal-Like Breast Cancer (Sox9-KO)

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. Mammary glands from three Sox9Fl/Fl animals and thee MMTV-iCre; Sox9Fl/Fl animals, in diestrus, were reduced to a single cell suspension sperately. From the Sox9Fl/Fl animals ER-negative luminal cells (Lin-,EpcamHi,CD49fLo,Sca1-negative) were sorted into Trizol LS. From the MMTV-iCre;Sox9Fl/Fl animals the same gating scheme was used, with the addition of the cells being ECFP+, to sort Sox9-null ER-negative luminal cells into Trizol LS. The resulting RNA was analyzed for gene expression differences by microarray.