Embryonic transcription factor SOX9 drives breast cancer endocrine resistance

Rinath Jeselsohn, MacIntosh Cornwell, Matthew Pun, Gilles Buchwalter, Mai Nguyen, Clyde Bango, Ying Huang, Yanan Kuang, Cloud Paweletz, Xiaoyong Fu, Agostina Nardone, Carmine De Angelis, Simone Detre, Andrew Dodson, Hisham Mohammed, Jason S. Carroll, Michaela Bowden, Prakash Rao, Henry W. Long, Fugen LiMitchell Dowsett, Rachel Schiff, Myles Brown

Research output: Contribution to journalArticlepeer-review

51 Scopus citations

Abstract

The estrogen receptor (ER) drives the growth of most luminal breast cancers and is the primary target of endocrine therapy. Although ER blockade with drugs such as tamoxifen is very effective, a major clinical limitation is the development of endocrine resistance especially in the setting of metastatic disease. Preclinical and clinical observations suggest that even following the development of endocrine resistance, ER signaling continues to exert a pivotal role in tumor progression in the majority of cases. Through the analysis of the ER cistrome in tamoxifen-resistant breast cancer cells, we have uncovered a role for an RUNX2-ER complex that stimulates the transcription of a set of genes, including most notably the stem cell factor SOX9, that promote proliferation and ametastatic phenotype. We show that up-regulation of SOX9 is sufficient to cause relative endocrine resistance. The gain of SOX9 as an ER-regulated gene associated with tamoxifen resistance was validated in a unique set of clinical samples supporting the need for the development of improved ER antagonists.

Original languageEnglish (US)
Pages (from-to)E4482-E4491
JournalProceedings of the National Academy of Sciences of the United States of America
Volume114
Issue number22
DOIs
StatePublished - May 30 2017
Externally publishedYes

Keywords

  • Breast cancer
  • Cistrome
  • Endocrine resistance
  • Estrogen receptor
  • SOX9

ASJC Scopus subject areas

  • General

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