Stem Cell Determinant SOX9 Promotes Lineage Plasticity and Progression in Basal-like Breast Cancer

• Published in: Cell reports (Cambridge) Vol. 31; no. 10; p. 107742
• Main Authors: Christin, John R., Wang, Chunhui, Chung, Chi-Yeh, Liu, Yu, Dravis, Christopher, Tang, Wei, Oktay, Maja H., Wahl, Geoffrey M., Guo, Wenjun
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 09.06.2020
• Subjects: Animals; basal-like breast cancer; bipotent cells; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Cell Lineage; Cell Plasticity - physiology; Cell Proliferation - physiology; DCIS progression; Disease Progression; Female; Humans; lineage plasticity; luminal stem progenitor cells; Mammary Neoplasms, Experimental - genetics; Mammary Neoplasms, Experimental - metabolism; Mammary Neoplasms, Experimental - pathology; Mice; Mice, Inbred C57BL; Mice, Knockout; Neoplastic Stem Cells - metabolism; Neoplastic Stem Cells - pathology; SOX9; SOX9 Transcription Factor - metabolism; Up-Regulation; basal-like breast cancer; DCIS progression; bipotent cells; lineage plasticity; SOX9; luminal stem progenitor cells
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2020.107742

Lineage plasticity is important for the development of basal-like breast cancer (BLBC), an aggressive cancer subtype. While 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 hybrid phenotypes. Why luminal progenitors are prone to BLBC transformation and what drives luminal-to-basal reprogramming remain unclear. Here, we show that the transcription factor SOX9 acts as a determinant for estrogen-receptor-negative (ER−) luminal stem/progenitor cells (LSPCs). SOX9 controls LSPC activity in part by activating both canonical and non-canonical nuclear factor κB (NF-κB) signaling. Inactivation of TP53 and RB via expression of SV40 TAg in a BLBC mouse tumor model leads to upregulation of SOX9, which drives luminal-to-basal reprogramming in vivo. Furthermore, SOX9 deletion inhibits the progression of ductal carcinoma in situ (DCIS)-like lesions to invasive carcinoma. These data show that ER− LSPC determinant SOX9 acts as a lineage plasticity driver for BLBC progression. [Display omitted] •SOX9 is required for luminal stem/progenitor cell (LSPC) activity•SOX9 enhances activation of canonical and non-canonical NF-κB pathways in LSPC•SOX9 upregulation drives luminal-to-basal reprogramming during BLBC formation•SOX9 deletion blocks progression of DCIS to invasive BLBC Basal-like breast cancer (BLBC) preferentially originates from ER-negative luminal stem/progenitor cells (LSPCs). Christin et al. show that the transcription factor SOX9 acts as a key regulator for these LSPCs. Inactivation of BLBC tumor suppressors co-opt SOX9 upregulation to promote luminal-basal reprogramming and tumor progression.