Journal Article

Embryonic transcription factor SOX9 drives breast cancer endocrine resistance

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

2017

Overview

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.

• Publisher: National Academy of Sciences
• Subject: Antagonists / Antineoplastic Agents, Hormonal - pharmacology / Biological Sciences / Breast - chemistry / Breast - metabolism / Breast cancer / Breast Neoplasms - chemistry / Breast Neoplasms - metabolism / Breast Neoplasms - physiopathology / Cancer / Cbfa-1 protein / Cell Proliferation - drug effects / Chromatin - metabolism / Drug Resistance, Neoplasm - drug effects / Embryos / Endocrine system / Endocrine therapy / Epithelial-Mesenchymal Transition / Estrogen receptors / Estrogens / Female / Humans / MCF-7 Cells / Medical Sciences / Metastases / PNAS Plus / Prescription drugs / Receptors, Estrogen - metabolism / Sox9 protein / SOX9 Transcription Factor - genetics / SOX9 Transcription Factor - metabolism / SOX9 Transcription Factor - pharmacology / Stem cell factor / Stem cells / Tamoxifen / Tamoxifen - pharmacology / Transcription factors