Embryonic transcription factor SOX9 drives breast cancer endocrine resistance.
Date
2017-05-15Author
Jeselsohn, R
Cornwell, M
Pun, M
Buchwalter, G
Nguyen, M
Bango, C
Huang, Y
Kuang, Y
Paweletz, C
Fu, X
Nardone, A
De Angelis, C
Detre, S
Dodson, A
Mohammed, H
Carroll, JS
Bowden, M
Rao, P
Long, HW
Li, F
Dowsett, M
Schiff, R
Brown, M
Type
Journal Article
Metadata
Show full item recordAbstract
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.
Collections
Subject
Breast
Chromatin
Humans
Breast Neoplasms
Tamoxifen
Receptors, Estrogen
Antineoplastic Agents, Hormonal
Cell Proliferation
Drug Resistance, Neoplasm
Female
SOX9 Transcription Factor
Epithelial-Mesenchymal Transition
MCF-7 Cells
Research team
Endocrinology
Language
eng
Date accepted
2017-04-28
License start date
2017-05-15
Citation
Proceedings of the National Academy of Sciences of the United States of America, 2017, 114 (22), pp. E4482 - E4491