Embryonic transcription factor SOX9 drives breast cancer endocrine resistance

被引：92

作者：

Jeselsohn, Rinath ^{[1
,2
,3
]}

Cornwell, MacIntosh ^{[1
]}

Pun, Matthew ^{[1
]}

Buchwalter, Gilles ^{[1
,2
]}

Mai Nguyen ^{[1
]}

Bango, Clyde ^{[1
]}

Huang, Ying ^{[1
]}

Kuang, Yanan ^{[4
]}

Paweletz, Cloud ^{[4
]}

Fu, Xiaoyong ^{[5
,6
,7
]}

Nardone, Agostina ^{[5
,6
,7
]}

De Angelis, Carmine ^{[5
,6
,7
]}

Detre, Simone ^{[8
]}

Dodson, Andrew ^{[8
]}

Mohammed, Hisham ^{[9
]}

Carroll, Jason S. ^{[9
]}

Bowden, Michaela ^{[1
]}

Rao, Prakash ^{[1
]}

Long, Henry W. ^{[1
]}

Li, Fugen ^{[1
]}

Dowsett, Mitchell ^{[8
,10
]}

Schiff, Rachel ^{[5
,6
,7
]}

Brown, Myles ^{[1
,2
,3
]}

机构：

[1] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA

[2] Dana Farber Canc Inst, Ctr Funct Canc Epigenet, Boston, MA 02215 USA

[3] Dana Farber Canc Inst, Breast Oncol Ctr, Boston, MA 02215 USA

[4] Dana Farber Canc Inst, Belfer Ctr Appl Canc Sci, Boston, MA 02215 USA

[5] Baylor Coll Med, Lester & Sue Smith Breast Ctr, Houston, TX 77030 USA

[6] Baylor Coll Med, Dan L Duncan Canc Ctr, Houston, TX 77030 USA

[7] Baylor Coll Med, Dept Mol & Cellular Biol, Houston, TX 77030 USA

[8] Royal Marsden Hosp, Ralph Lauren Ctr Breast Canc Res, London SW3 6JB, England

[9] Univ Cambridge, Li Ka Shing Ctr, Cambridge Inst, Nucl Transcript Factor Lab,Canc Res UK, Cambridge CB2 0RE, England

[10] Inst Canc Res, Breast Canc Now Toby Robins Res Ctr, London SW7 3RP, England

来源：

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA | 2017年 / 114卷 / 22期

关键词：

estrogen receptor; breast cancer; cistrome; endocrine resistance; SOX9; ESTROGEN-RECEPTOR-ALPHA; GENOME-WIDE ANALYSIS; GENE SET ENRICHMENT; POSTMENOPAUSAL WOMEN; EXPRESSION ANALYSIS; ANDROGEN RECEPTOR; RANDOMIZED-TRIAL; IN-VITRO; RUNX2; TAMOXIFEN;

D O I：

10.1073/pnas.1620993114

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页码：E4482 / E4491

页数：10

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