Author:
Jeselsohn Rinath,Cornwell MacIntosh,Pun Matthew,Buchwalter Gilles,Nguyen Mai,Bango Clyde,Huang Ying,Kuang Yanan,Paweletz Cloud,Fu Xiaoyong,Nardone Agostina,De Angelis Carmine,Detre Simone,Dodson Andrew,Mohammed Hisham,Carroll Jason S.,Bowden Michaela,Rao Prakash,Long Henry W.,Li Fugen,Dowsett Mitchell,Schiff Rachel,Brown Myles
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 a metastatic 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.
Funder
Susan G. Komen for the Cure
HHS | NIH | National Cancer Institute
Royal Marsden NIHR Biomedical Research Centre
Publisher
Proceedings of the National Academy of Sciences