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Proc Natl Acad Sci U S A. 2017 May 30;114(22):E4482-E4491. doi: 10.1073/pnas.1620993114. Epub 2017 May 15.

Embryonic transcription factor SOX9 drives breast cancer endocrine resistance.

Author information

1
Department of Medical Oncology, Dana Farber Cancer Institute, Boston, MA 02215; myles_brown@dfci.harvard.edu rinath_jeselsohn@dfci.harvard.edu.
2
Center for Functional Cancer Epigenetics, Dana Farber Cancer Institute, Boston, MA 02215.
3
Breast Oncology Center, Dana Farber Cancer Institute, Boston, MA 02215.
4
Department of Medical Oncology, Dana Farber Cancer Institute, Boston, MA 02215.
5
Belfer Center for Applied Cancer Science, Dana Farber Cancer Institute, Boston, MA 02215.
6
Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030.
7
Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030.
8
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030.
9
Ralph Lauren Centre for Breast Cancer Research, Royal Marsden Hospital, London, SW3 6JB, United Kingdom.
10
Nuclear Transcription Factor Laboratory, Cancer Research UK, Cambridge Institute, Cambridge University, Li Ka Shing Centre, Cambridge, CB2 0RE, United Kingdom.
11
The Breast Cancer Now Toby Robin's Research Centre, Institute of Cancer Research, London, SW7 3RP, United Kingdom.

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.

KEYWORDS:

SOX9; breast cancer; cistrome; endocrine resistance; estrogen receptor

PMID:
28507152
PMCID:
PMC5465894
DOI:
10.1073/pnas.1620993114
[Indexed for MEDLINE]
Free PMC Article

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