Pathiraja Thushangi N, Nayak Shweta R, Xi Yuanxin, Jiang Shiming, Garee Jason P, Edwards Dean P, Lee Adrian V, Chen Jian, Shea Martin J, Santen Richard J, Gannon Frank, Kangaspeska Sara, Jelinek Jaroslav, Issa Jean-Pierre J, Richer Jennifer K, Elias Anthony, McIlroy Marie, Young Leonie S, Davidson Nancy E, Schiff Rachel, Li Wei, Oesterreich Steffi
Graduate Program in Translational Biology and Molecular Medicine, Baylor College of Medicine, Houston, TX 77030, USA.
Sci Transl Med. 2014 Mar 26;6(229):229ra41. doi: 10.1126/scitranslmed.3008326.
Resistance to aromatase inhibitors (AIs) is a major clinical problem in the treatment of estrogen receptor (ER)-positive breast cancer. In two breast cancer cell line models of AI resistance, we identified widespread DNA hyper- and hypomethylation, with enrichment for promoter hypermethylation of developmental genes. For the homeobox gene HOXC10, methylation occurred in a CpG shore, which overlapped with a functional ER binding site, causing repression of HOXC10 expression. Although short-term blockade of ER signaling caused relief of HOXC10 repression in both cell lines and breast tumors, it also resulted in concurrent recruitment of EZH2 and increased H3K27me3, ultimately transitioning to increased DNA methylation and silencing of HOXC10. Reduced HOXC10 in vitro and in xenografts resulted in decreased apoptosis and caused antiestrogen resistance. Supporting this, we used paired primary and metastatic breast cancer specimens to show that HOXC10 was reduced in tumors that recurred during AI treatment. We propose a model in which estrogen represses apoptotic and growth-inhibitory genes such as HOXC10, contributing to tumor survival, whereas AIs induce these genes to cause apoptosis and therapeutic benefit, but long-term AI treatment results in permanent repression of these genes via methylation and confers resistance. Therapies aimed at inhibiting AI-induced histone and DNA methylation may be beneficial in blocking or delaying AI resistance.
对芳香化酶抑制剂（AI）的耐药性是雌激素受体（ER）阳性乳腺癌治疗中的一个主要临床问题。在两种AI耐药的乳腺癌细胞系模型中，我们发现了广泛的DNA高甲基化和低甲基化，发育基因的启动子高甲基化更为富集。对于同源框基因HOXC10，甲基化发生在一个CpG岛岸，其与一个功能性ER结合位点重叠，导致HOXC10表达受到抑制。尽管短期阻断ER信号通路可使两种细胞系和乳腺肿瘤中的HOXC10抑制得到缓解，但这也导致EZH2同时募集和H3K27me3增加，最终转变为DNA甲基化增加和HOXC10沉默。体外和异种移植中HOXC10减少导致凋亡减少并引起抗雌激素耐药。支持这一点的是，我们使用配对的原发性和转移性乳腺癌标本表明，在AI治疗期间复发的肿瘤中HOXC10减少。我们提出了一个模型，其中雌激素抑制凋亡和生长抑制基因如HOXC10，促进肿瘤存活，而AI诱导这些基因导致凋亡和治疗益处，但长期AI治疗会通过甲基化导致这些基因永久抑制并产生耐药性。旨在抑制AI诱导的组蛋白和DNA甲基化的疗法可能有助于阻断或延迟AI耐药。
