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

John R. Christin, Chunhui Wang, Chi Yeh Chung, Yu Liu, Christopher Dravis, Wei Tang, Maja H. Oktay, Geoffrey M. Wahl, Wenjun Guo

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Article number107742
JournalCell Reports
Volume31
Issue number10
DOIs
StatePublished - Jun 9 2020

Keywords

  • DCIS progression
  • SOX9
  • basal-like breast cancer
  • bipotent cells
  • lineage plasticity
  • luminal stem progenitor cells

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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