Embryonic transcription factor SOX9 drives breast cancer endocrine resistance
Embryonic transcription factor SOX9 drives breast cancer endocrine resistance
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DOI：
10.1073/pnas.1620993114
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发表时间：
2017-05-30
影响因子：
11.1
通讯作者：
Brown, Myles
中科院分区：
文献类型：
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作者：
Jeselsohn, Rinath;Cornwell, MacIntosh;Brown, Myles
雌激素受体（ER）驱动大多数腔型乳腺癌的生长，是内分泌治疗的主要靶点。虽然ER阻断药物如他莫昔芬是非常有效的，一个主要的临床限制是内分泌抵抗的发展，特别是在转移性疾病的设置。临床前和临床观察表明，即使在内分泌抵抗的发展之后，ER信号传导在大多数情况下继续在肿瘤进展中发挥关键作用。通过对他莫昔芬耐药乳腺癌细胞中ER顺式组的分析，我们发现了RUNX 2-ER复合物的作用，该复合物刺激一组基因的转录，包括最显著的干细胞因子SOX 9，其促进增殖和易位抑制表型。我们发现，SOX 9的上调足以引起相对内分泌抵抗。在一组独特的临床样品中验证了SOX 9作为与他莫昔芬抗性相关的ER调节基因的获得，这支持了开发改进的ER拮抗剂的需要。
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.